Canonical
changes during aging
Classification
of dementias
Symptoms
of dementia
1) Clinical manifestations
2)
Cellular pathology
3)
Cholinergic deficits, relationship between cholinergic loss, pathological
lesions and
dementia
4) Other neuropathological-neurochemical
abnormalities
5) Progression of the disease
6) Pathology of the aging brain in
relation to AD
7) Clinical-pathological correlations
8) Etiology and genetics of AD
9) Transgenic mice models
10) Pathogenesis
11) Therapy in AD
AGING AND
DEMENTIAS
Foundation lecture
OVERVIEW OF AGING
Despite
individual variations in life spans and detail of aging, there is in most
species an overall consistency in the characteristics of aging that can be
described as a canoniocal pattern of aging.
For example, finite numbers of ovarian oocytes are found in virtually
all mammals; an age-related loss of germ cells and hormone-producing follicles
is the main cause of sterility at midlife. As a consequence of the depletion of
hormone producing follicles, many female mammals experience accelerated
osteoporosis, which is best seen in humans and laboratory mice and rats. However, not all irreplacable cells are lost
during aging. For example, the GnRH containing neurons in the hypothalamus,
which are the proximal drivers of the ovulatory surges of gonadotropins, show
no evidence of loss according to counting. Moreover, the obligatory neuron
death during aging in the absence of Alzheimer’s disease (AD) continues to be
controversial. Other canonic changes of mammals are the accumulation of
lipofuscins or aging pigments in non-dividing cells, the decrease of striatal
D2 receptors and the proliferation of smooth muscle cells in blood vessels walls.
A major objective of biomedical gerontology is to identify the canonical age
changes at molecular, cellular and physiological levels. From this slowly
emerging normative or canonical pattern, it will become increasingly possible
to construct powerful hypotheses about the interrelationships and causal
chains. Historically, it was thought
that the primary contribution to age-related cognitive decline were massive
cell loss. More recent studies suggest, that most age-associated behavioral
impairements result from-region-specific changes in dendritic morphology,
cellular connectivity, Ca2+ dysregulation, gene expression that affect
plasticity and ultimately alter network dynamics of neural ensembles that
support cognition.
1) Issues of neuron loss
versus atrophy and astrocytic hyperactivity in evaluating molecular aging
changes
It
is well known that most neurons in the mammalian brain are postmitotic and
therefore at risk for irreversible demage. Brain atrophy has long been accepted
consequence of aging in humans. Originally depicted by gross brain weights and
then by conventioanl X-ray and other tomographic techniques, it is amply
confirmed that decreases in cranial volume occupied by brain parenchyma are
accompanied by complementary increases in the volume occupied by cerebral
spinal fluid. Although brain shrinkage was not originally believed to be
selective for regions, longitudinal studies of aging subjects by CT revealed
that cortical atrophy was selective and restricted to certain areas.
Brain Weight and Volume. The decline in brain
weight with age is significant but the onset of reduction is unclear. The
volume of the brain in the 8th decade is reduced by 6%-10% versus the third
decade. The age related changes are more prominent in the frontal lobe which
shows a 10% reduction in volume and 15% reduction in cortical thickness. The
corpus callosum is decreased in volume by 12-17%, with accentuation in the
anterior 2/5th because of the reduction of fronto-temporal interhemispheral
fibers.
Neuronal Counts. The widely held public belief in the
inevitability of neuron loss during normal aging is also being extensively
revised. The gloomy estimate of 100,000 neurons lost per day does not seem to
be as plausible as it once did in view of more recent sophisticated
measurements. Neuronal shrinkage or atrophy could account for some of the
confusion surrounding neuronal losses with age.
Cerebral Cortex. Total neuronal population is not significantly
changed. However, there is a severe loss of neurons with more severe involvement
of the frontal cortex. In aged-non human primates, there is a 30% reduction in
neuron numbers in all layers in area 8A of the dorsolateral prefrontal cortex
(Smith et al., 2004). The salient age-related change is shrinkage of large neurons
between 10-35%, with consequently increasing numbers of small neurons. Aging
predominantly involves the frontal lobes. The comparatively stable numbers of
neocortical neurons in normal aging are in contrast to the extensive neuronal
depletion in AD ranging from 40-60% associated with up to a 400% increase in
astroglia. Nucleolar shrinkage probably represents reduced ribosomal RNA
synthesis and possibly changes in ribosomal gene regulation. Substantial
decline in the density of synapses, marked changes in dendritic architecture
have been documented in the frontal lobe during normal aging (Peters et al.,
1998).
Hippocampus. While older manual
cell counts revealed neuronal losses of 20-30% in total H with one up to 6%
cell loss per decade, more recent automatized studies showed only mild or no
significant effect of age on pyramidal cell density. This is in contrast to a
significant cell decrease in AD ranging from 19% in presubiculum to 44% in the
CA1 and subiculum (S) associated with severe regression of dendritic extent. In
the olfactory bulb (
Interestingly, there is
an increase (15%) of gap junctions between granule cells, and between neurons
in the CA1 and CA3. The number of Schaffer collateral-CA1 synapses did not
change. There is also a reduction in the postsynaptic density of the so-called
perforated synapses in the CA1 area.
Subcortical nuclei. Striatum shows a decrease in total volume of
12% but no significant neuronal loss with age. The striatonigral DA system
shows mild damage with neuronal losses particularly in the substantia nigra
zona compacta (SNC) dorsal tier. In contrast, in PD mainly the ventral tiers
are affected. Locus coeruleus (LC): after the age of 65 a total of 24-54% with
predominant damage to rostral parts projecting to neocortex and hippocampus
(H). In Alzheimer’s disease (AD) there is 40-80% cell loss. The serotoninergic
dorsal raphe shows little variation
during aging. In contrast, in AD the depletion of large neurons ranges from
30-70%. For the cholinergic forebrain controversial data are available. While
McGeer et al (1984) estimated a 70% loss of large cholinergic neurons, more
recent studies did not show significant age-dependent variations in cortical
ChAT activity. In AD, magnocellular NBM cell loss ranges from 15-70%.
As
mentioned, a hallmark of aging in many brain regions is a progressive atrophy
of neurons, but the relationship to neuron death is unclear. The nucleolar
shrinkage in the remaining neurons of the SN in PD is particularly puzzling
because lesions of this pathway induced hyperactivity in the remaining neurons
in young rats. For example, nigral lesions increased the synthesis and release
of DA at the terminals or increased TH. In regard to increased DA metabolism,
the opposite changes of the TH-mRNA in its cell body and of DA synthesis and
release at its striatal terminals imply a dichotomous regulation. It is
possible that the efficiency of TH mRNA translation increased several fold to
compensate for reduced mRNA.
The
role of reactive glia in the aging brain is receiving much attention. Several
reports show 10-30 % increases in glial cell mass or number with age in the
rodent brain. Possibly, an increase in neural atrophy, resulting in a decrease
in neuronal volume, is accompanied by a compensatory increase in the number or
volume of glial cells. It is attractive to suppose that neuronal atrophy and
loss might induce astrocyte (perhaps microglial) reactivity and proliferation
during aging, yet the consequences of these events remain a matter of
conjecture. After brain injury in adults, astrocytes remove debris and provide
growth factors for neurite outgrowth.
Astrocytes may have a role in guiding axon growth which is pertinent to
synaptic plasticity. On the other hand,
injury-induced reactive gliosis in the adult brain may impair neural function.
Prolonged glial hyperactivity might result in physical barriers from glial
scars. Both the protein and the mRNA for GFAP are increased in the hippocampus
after deafferentation.
2) Neurogenesis in adult
animals
Until
recently, brain neurons were thought to be irreplaceable. The challenge to the
‘no new neuron’ dogma came first by the study of Altman and Das in 1965 in rats
showing that newly born neurons appear in the dentate gyrus. Nearly 20 years
later Nottebohm and coworkers discovered the addition of new neurons to the
vocal centers in canaries. Adult
neurogenesis continue to be a very controversial topics. For example, is
neurogenesis outside the dentate gyrus and olfactory bulb also in the frontal
cortex in primates, etc. Apparently stress and depression suppress
neurogenesis, whereas exercise, stimulating environment and antidepressant
drugs give it a boost (Gage, Gould, etc).
Part of the controversy stems from the lack of unequivocal evidence for
neuronal versus glial cell proliferation. Also, it is unclear how long
neurogenesis lasts and how neurogenesis keeps in balance with neuronal death,
preservation of memory traces, etc
3) Biophysical
properties of aged neurons, LTP, LTD
In
all subregions of the hippocampus, most electrical properties remain constant
over the lifespan. These include resting membrane potential, membrane time
constant, input resistenance, threshold to reach action potential and the width
and amplitude of Na action potentials. Numerous studies, however, have shown an
increase in Ca2+ conductance in aged neurons. CA1 pyramidal cells in the aged
hippocampus have an increased density of L-type Ca-channels that might lead to
disruption in Ca-homeostasis, contributing to plasticity deficits that occur
during ageing. Neurons in the prefrontal cortex (PFC) of aged monkeys,
similar to CA1-CA3 pyramids have a
significantly larger AHP compared to
young neurons that relate in part to increases in Ca2+ conductance. There are
subtle deficits in old aged rats in the induction or maintenance of LTP and LTD
in the hippocampus (Burke and Barnes, 2006).
4) Age-related changes
in gene expression
It
is known that the maintenance of LTP requires gene expression and de novo
protein synthesis. In behaviorally characterized rats, gene expression
alterations in area CA1 were found to correlate with age-related cognitive
decline. The behaviorally relevant upregulated genes included several that are
associated with inflammation and intracellular Ca2+ release pathways, whereas genes
associated with energy metabolism, biosynthesis and activity-regulated
synaptogenesis were downregulated. Arc and Narp were two of the genes that were
shown to be downregulated. Narp and Arc are effector IEGs. After transcription,
Narp mRNA translocate to the synapse, where it is released and may act to
cluster AMPA receptors on the postsynaptic membrane. After transcription, Arc
mRNA localizes selectively to the region of the dendrite that receive the
synaptic input that initiated transcription, and is proposed to be involved in
the structural rearrangement of activated dendrites. The results should be
interpreted with caution, however, as the data reflect resting levels of gen
expression. In aged rats, granule cells of the dentate gyrus, but not the pyramidal
cells of the CA3-CA1 area, have significantly smaller proportion of neurons
that express Arc following spatial exploration. Also, in the CA1 area of young
rats CA1 cells have higher levels of c-fos mRNA compared with old animals,
although the same proportion of cells express c-fos (Burke and Barnes, 2006).
5)Dynamics of aged
neural ensembles
It
is widely agreed that modifiable neuronal ensembles support cognition.
Therefore, alterations in these networks could be responsible for the
behavioral impairments observed with ageing. In young rats, CA1 place fields
expand asymmetrically during repeated route following. The magnitude of this place
field expansion, however, significantly decreases in aged rats. It is likely
that this age-associated reduction in experience-dependent plasticity is due to
LTP deficits, as it does not occur when the NMDA receptor antagonist CPP is
administered to young rats. In addition to age-related alterations in
experience-dependent place-field expansion, the maintenance of place maps also
differs between young and adult animals. For example, rats showing poor
performance in a spatial task after returned to the familiar environment is
correlated to retrieval of an incorrect map. A probable mechanism for map
retrieval failures is defective LTP in aged rats. In young rats, blockade of NMDA receptors or
protein synthesis inhibition has been shown to result in map retrieval error
when the rat is returned to the same environment (Burke and Barnes, 2006).
6) Impaired DNA repair in
ageing
The
possibility of age-related changes in the structure of genomic and
mitochondrial DNA and the fidelity of its replication continue to be a very
fruitful topics in molecular gerontology. The classic somatic mutation
hypothesis of aging, now more than 40 years old, proposed that age-related
accumulations of mutations in somatic cells account for the limit of life span
(Hasty et al., 2003). Genetic defects in genome maintenance, driven by
oxidative damage (see below) is a primary cause of aging. Mitochondrial DNA has
a much higher mutation frequency than that of nuclear DNA in humans. Evidence
indicates that mitochondrial DNA mutations cause deficiencies in respiration
and ATP synthetase complexes.
As
an example of somatic mutations, several laboratories have shown the
spontaneous curing of a germ-line recessive mutations in the Brattleboro (B)
rat strain; here a frame-shift mutation that prevents processing of the VP
(vasopressin) prohormone. During aging, there is a progressive increase in cells
containing normal protein. At 1 month of age, only 0.1 % of the neurons produce
normal VP, but by 20 month of age, approx. 3% of the total VP neurons making
the protein. The reverse of this germ-line mutation in B rats occurs through
somatic mutations that correct the frameshift and appear to occur through
mini-rearrangement of the 3’ region of the G deletion.
7) Accumulation of
damaged proteins
The
simplistic theoretical hope that aging might be accounted for by randomly
accumulated errors in macromolecular synthesis is clearly not supported.
However, some evidence suggests that the rates of RNA and protein synthesis are
altered during adult life. An example of
germane to the neurobiology of aging is the B-amyloid precursor protein mRNA
(APP). Three differentially spliced forms of APP mRNA are identified by the
lengths of the polypeptides that each encodes: 695, 751 and 770. The APP 751 transcript has drawn particular
attention because it includes a Kunitz protease inhibitor motif; inhibition of
protease activity could be a factor in the accumulation of B-amyloid plaques in
the brain. Neurons in the cortex and hippocampus contain the 696 and 751 forms.
Amyloid plaques are not unique to AD and occur with considerable variability in
the brains of normal aged individuals. Possible increases in the relative
prevalence of the 751 transcript in relation to plaques and NFT-s in AD are
controversial.
The
list of specific molecules that increase or decrease in the brain during aging
is growing: As with cell atrophy, they are region and cell specific. For
example, the hypothalamic content of POMC mRNA decreased by 30%, GFAP mRNA
increases and the Thy1 antigen mRNA decreases in the hippocampus.
The
search for other mRNAs that change during aging and AD has involved
differential screening of cDNA libraries made from intact and deafferented rat
hippocampus polyRNA. These cloning
strategies were designed to isolate mRNAs that are increased or decreased at a
specific time after lesion. After a
change in a particular mRNA is confirmed by Northern blot, sequence analysis
identified by the clone. By this approach 25 mRNAs were identified as
responding to deafferentation. ApoE, alfa1tubulin, and synaptosome-associated
proteins, Alfa1tubulin mRNA was also shown to increase in AD. In addition to
these structural molecules, inflammatory mediator, transforming growth factorB1
increases in the hippocampus after EC lesion.
The appearance of vimentin and alfa1tubulin mRNAs has led to the hypothesis
that proteins normally present only during development may be induced by
degeneration. MAPs are expressed in a
specific sequence during development, in brains from AD patients, in the rat
hippocampus after EC lesion and in reactive astrocytes. The MAPs are
constituents of senile plaques (SP) and neurofibrillary tangles (NFT). A decrease in the presynaptic growth
associated protein GAP-43, a substrate for protein kinase C phosphorylation
demonstrated in brains from patients with AD suggest that abnormal
synaptogenetic responses are present in AD.
8) Increased free
radical damage during aging
Metabolic
by-products called reactive oxygen species continually damage cellular
macromolecules, including DNA. More than 100 different types of oxidative DNA
lesions have been described. These lesions disrupt vital processes such s
transcription and replication, which may cause cell death or growth arrest or
may induce mutations that lead to cancer. Incomplete repair of such damage
would lead to its accumulation over time and eventually result in age-related
deterioration. A number of observations support the free radical theory,
including the discovery that dietary restriction delays aging and extends
life-span in wide range of rodents and other species, possibly by reducing free
radical damage. The notion that genomic and mitochondrial DNA could be a major
target of continual free radical attack over time is supported by the recent
observation that genetic lesions accumulate with age and that dietary
restriction reduces this accumulation in rodents (see review of aging research
in Science, 299/5611,
9) Slowing of axonal transport
Slower
axoplasmic flow in peripheral nerves of aged rats is consistent with reduced
rates of synthesis. Slow axoplasmic transport is responsible for the movement
of cytoskeletal proteins within the axon. Observations that plasticity is
impaired in the aging rodent brain and may be aberrant in AD suggest that slow
axonal transport may play a role in these events.
10) Effects of hormones: pituitary, ovary,
adrenal cortex
Adrenal
corticosteroids are also implicated in neurodegenerative changes during brain
aging, particularly in the rat hippocampus. Among others, the age -related loss
of large neurons with receptors for corticosteroids and the hyperactive glia in
the hippocampus are retarded by chronic adrenalectomy and are prematurely
induced in young rats by sustained exposure to corticosteroids. These findings
suggest that under some circumstances, sustained stress has adverse effects on
brain neurons.
Certain mutations (Propdf and Pit1) impede
pituitary production of GH, TSH and prolactin; reduce growth rate and adult
body size and increase life-span by 40-60%. Without GH, the synthesis of
circulating IGF-1 is suppressed (insulin-like growth factors). Reduced
insulin/IGF activity is commonly associated with extended longevity of
nematodes, flies and mice (Tatar et al., 2003). Estrogen and plasticity.
Estrogens promote axonal and dendritic plasticity in the hippocampus of male as
well as female brains (McEwen et al., 1997). In female mice, ovariectomy
severely impairs the reactive hippocampal synaptogenesis that follows
entorhinal damage. This effect is reversed by estrogen replacement.
Postmenopausal estrogen deficiency may thus suppress the potential for
neuroplasticity.
11) Animal
models of cognitive and neurobiological aging
Rats in the Morris water maze (MWM) learn the
escape location in relation to the configuration of cues surrounding the
testing apparatus and this capacity requires the functional integrity of the hippocampal
formation. During aging the performance in the MWM is declining, although
there is a substantial variability among the aged rats and about half of them
learn as well as young adults.
Whereas
the hippocampus is crucially involved in spatial and episodic memory, the prefrontal
cortex (PFC) is necessary for working memory (WM) and executive functions. WM
can be measured using the delayed non-matching to sample task. Aged rats and
non-human primates show time-dependent deficits on DNMS. Executive functions
are measured with the Wisconsin Card Sort Task. Aged humans are impaired on the
WCST and make more perseverative errors.
Definitions. Dementia usually denotes a clinical
syndrome composed of failing memory and
impairment of at least one other cognitive function due to chronic
progressive degenerative disease of the brain. The involvement of multiple
capacities distinguishes dementia from other disorders such as amnesia and
apahasia, that affect a single functional domain (memory or language). The term
includes a number of closely related syndromes that are characterized not only
by intellectual deterioration but
also by certain behavioral abnormalities
and changes in personality. The
symptoms are different on the basis of their speed of onset, rate of
progression, severity or duration. There are several states of dementia of
multiple causation and mechanism and that a diffuse degeneration of neurons,
albeit, common, is only one of the many causes. Therefore it is more correct to
speak of dementias. Most have an insidious onset and develop slowly over a
period of many years. These include Alzheimer’s Disease (AD), Parkinson’s
Disease (PD), Huntington’s disease (HD), frontotemporal dementia (FTD).
Creutzfeldt-Jacob disease also develops insidiously, but is distinquished by a
very rapid rate of progression, often spanning a year or less from the onset of
the dementia to death. Multi-infarct dementia follows still another pattern.
Initial cognitive symptoms develop acutely, but in this case the clinical
course typically proceeds in a stepwise fashion over many years, with periods
of relative stability punctuated by abrupt deterioration.
Cortical-Subcortical
Dementia. In
1974, Albert introduced the term ‘subcortical dementia” to describe the clinical picture of intellectual impairment found
in progressive supranuclear palsy (PSP). The dementia was characterized by
forgetfullness, slowness of thought process or bradyphrenia, alterations in
mood and personality (particularly apathia and depression), plus a reduced
ability to manipulate acquired knowledge.
This clinical picture was contrasted with the frank amnestic, aphasic,
apraxic and agnostic disorders of AD and other “cortical dementias” such as
Pick disease. Subsequently, the concept of subcortical dementia broadened to include
a variety of neurological disorders in which the primary pathology was believed
to be subcortical. These included Huntington’s disease (HD), Parkinson’s
disease (PD) and Wilson’s disease. While the pathology of PSP is almost
exclusively subcortical, in both PD and HD significant cortical changes can be
observed, particularly in patients with intellectual deterioration. On the
other hand, subcortical pathology is known to be typical of AD. As Whitehouse
(1986) points out, “the use of the terms ‘subcortical’ and ‘cortical’ tends to
emphasize the independence of these regions in the brain”. In fact, the dense
pattern of neuronal interconnections between cortical and subcortical regions
suggests that the functional organization of the brain does not respect such
conventional anatomical distinctions. Animal studies have shown that in
functional systems which link cortical and subcortical regions, lesions at any
level can produce seemingly identical behavioral deficits. Albert himself
(1978) considered this issue and concluded that a better label for subcortical
dementia may be “frontosubcortical dementia”. Indeed, when considering the
cognitive impairments in AD, HD, PD and PSP, using simple neuropsychological
tests, there is little consistent evidence for separating the four diseases
into two broad categories of cortical and subcortical dementia. However, with
the increased use of more sophisticated tests, the weight of evidence suggest
that each disease has its own characteristic picture of impairment, with a
small number of shared functions.
Symptoms of dementia
Memory: The gradual
development of forgettfulness is a prominent early symptom. Proper names are no
longer remembered, the purpose of an errand is forgotten, appointments are not
kept, a recent conversation or social event has been forgotten. The patient may
get lost, even along habitual routes. Day-to-day evens are not recalled. At the
early stage, memory for the remote past is relatively preserved in AD,
impairment is expressed in maintaining memories fro recent past. By comparison,
patients with HD display a different profile in which declarative memory is
relatively spared against a substantial impairment in procedural or habit-like
memory that is thought to rely on cortico-striatal circuitry.
Visuo-spatial
skills
Attention: the patient is easily
distracted by every passing incident.
Language: Language functions
tend to suffer almost from the beginning. Vocabulary becomes restricted and
conversation, rambling and repetitious. The patient gropes for proper names and
common nouns and no longer formulates ideas with well constructed phrases or
sentences. Instead, there is a tendency to resort to cliches, stereotyped
phrases which may hide the underlying defect during conversations. Subsequently,
more severe degrees of aphasia, dysartria, palialia and echolalia may be added
to the clinical picture.
Executive
function (frontal lobe syndrome): Loss of
capacity of the individual to act purposefully, to think rationally, and
to deal effectively with his/her environment. No longer is it possible for the
patient to think about or discuss a problem with customary clarity, and he/she
fails to comprehend all aspect of a complex situation. One feature of a situation that some
relatively unimportant event may become a source of unreasonable concern or
worry. Judgement becomes impaired. As a rule, these patients have little or no
realization of such changes within themselves: they lack insight
Emotional
instability:
Petulance, agitation, shouting, whining if restrained, loss of social grace,
loss of the capacity to tolerate frustration and restrictions. The first
abnormality may be in the nature of emotional instability taking the form of
outbursts of anger, tears or aggressiveness, loss of the capacity to express
feelings and impulses.
Progression of dementia. At certain phases of the
illness, suspiciousness or frank paranoia may develop. Visual and auditory
hallucinations may be added. As the condition progress, all intellectual
faculties are impaired, but memory most of all. Patients may fail to recognize
their relatives or to recall their names. Apractognosias may be prominent and
these defects may alter the performance of the simplest task. There is a kind
of psychic inertia. All movements are slow, sometimes suggesting an oncoming
Parkinson’s disease. Sooner or later the gait becomes altered in a
characteristic manner. In the later stages, physical deterioration is
inexorable. Any febrile illness, drug intoxication, or metabolic upset is
poorly tolerated, leading to severe confusion, stupor or coma, an indication of
the precarious state of cerebral compensation. Finally, these patients remain
in bed and succumb to pneumonia or to other intercurrent infection. Some
patients, become virtually decorticate, totally unaware of their environment,
unresponsive, mute and incontinent.
Naturally, every case does not follow the exact sequence outlined above.
Impaired facility with language, in other impairment of retentive memory with
relatively intact reasoning may be the dominant feature. Gait disorder may
occur early, particularly in patients in whom the dementia is superimposed on
Parkinson disease, cerebellar ataxia or ALS.
Alzheimer's disease (AD) currently
afflicts over 4 million Americans and it is the eights leading cause of death.
AD is the most common form of dementia, accounting for about 50% of all cases.
The prevalence of the disease is tightly coupled to age and increases after the
fourth decade of life. The prevalence of AD doubles approximately every 5 years
after the age 60. The disease affects about 1% of persons aged 60-64 and up to
40% among those 85 years older. Definitive diagnosis of AD is available only
at autopsy, although the increased use of imaging and genetic methods promises
an early diagnosis (DeKosky and Marek, 2003).
A variety of risk factors increase the
likelihood of developing AD. Age is the most potent of the known risks. Female
gender is also a risk factor; the ratio of affected woman to men is 1.2:1 to 1.5-1.
A history of head trauma and a low level of educational attainment are
additional risks. Genetic risk factors for the late-onset AD have been identified. The most important type
of these is the ApoE-4 allele. The lifetime risk of AD for an individual
without the e4 allele is about 10%, whereas for an individual carrying at least
one allelele is 30%. However, determining the ApoE genotype cannot be regarded
as a diagnostic test for AD, since some individuals who do not bear the risk
allelele develop the illness, and some who
have the allelel are spared the disease. Several causative mutations for
AD have been identified. These are transmitted in an autosomal dominant fashion
with complete penetrance; those inheriting the mutation will manifest the disease
in the course of their lifetime. Mutations in the amyloid precursor protein
gene (chromosome 21), presenilin 1 gene (chr. 14), or the presenilin 2 gene
(chr. 1), produce familial AD. Inherited AD is rare, accounting for <5% of
all cases.
Numerous investigations have attempted to
isolate the one aspect of the neuropathology that is most closely associated
with the cognitive deficits. Such claims have been made for the amyloid
plaques, neurofibrillary tangles, neuronal loss, synaptic loss and cholinergic
depletion. Despite our increased understanding of pathological processes
present in AD, the primary cause(s) and the pathophysiology is (are) not clear.
Despite numerous attempts, a unitary theory that can account for all the
clinical and neuropathological features has failed to emerge.
1)
Clinical manifestations
AD occurs in middle or late life and is
characterized by a progressive dementia. Typically, cognitive impairments
appear insidiously. Some fluctuations may occur in individual patients, but
more commonly, impairments in memory, language, praxis, visuo-spatial
perception, judgement, and behavior become progressively more disabling (see
Alois Alzheimer’s first description of the disease in 1907). Individuals with
early onset disease usually have the most severe clinical, histopathological
and neurochemical abnormalities. Dynamic
imaging studies of AD have demonstrated reductions in regional cerebral blood
flow, oxygen consumption, glucose metablolism, and protein synthesis.
Correlations have been demonstrated between results of these imaging studies
and characteristics of neuropsychological deficits. For example, patients with
language impairments exhibit reduced metabolic activity in the left
parietal-temporal region. These focal signs have been attributed to an
admixture of pathologies including lesions of subcortical neuronal systems
afferent to cortex and disease of intrinsic cortical cells. The global dementia
and diffuse reductions in electrical activity and metabolism occuring in later stages
of the disease are believed to reflect bilateral distribution of these
processes. Using PET and non-toxic tracers, B-amyloid can be visualized also in
the living brain. Other studies suggest that with longitudinal MRI studies,
shrinking hippocampal volume may be an early diagnostic sign of AD. Serum
levels of B-amyloid elevated in the blood of people with APP or presenilin
mutations, however the sensitivity and specificity of these tests has been
limited. Plate summarizes the common types of dementing
illnesses and their relative frequency. The onset of AD is not abrupt and
patients pass through a phase of mild cognitive impairment (MCI) during which
they exhibit cognitive deficits that are distinguishable from normal aging, but
not meet the full criteria for AD.
2)
Cellular pathology
The current criteria for the pathologic
diagnosis of AD require the presence of both neuritic plaques and
neurofibrillary tangles. The pathologic diagnosis is confirmed when there are
frequent neuritic plaques using the criteria developed by the Consortium to
Establish a Registry for Alzheimer’s Disease (CERAD) and neruofibrillary
tangles in an abundance grade by the Braak and Braak approach as stage V-VI. AD selectively affects several
subcortical neuronal populations, including nerve cells of the basal forebrain
cholinergic system, the brainstem locus coeruleus (LC) as well as certain
neurons in amygdala, hippocampus and neocortex. These at-risk neuronal
populations show several types of pathology, including neurofibrillary
tangles and neuritic or senile
plaques.
Neurofibrillary tangles (NFT) (Plate ). These perikaryal (intracellular)
inclusions are composed of densely packed fibers. Electron microscopically the
tangles consist of highly insoluble
protein polymers appearing as 10 nm paired helical filaments (PHF), which are
frequently associated with 15 nm straight and 10 nm neurofilaments.
Immunocytochemical studies suggest that PHF are composed of a cytoskeletal
protein, the
microtubule-associated protein tau
(MAPT) that is normally present in axons, but not in cell bodies. Tangle-containing
neurons eventually die. Nearly all individuals above age 65 have a few NFT-s in
their brains (Braak and Braak, 1996). Whenever a brain contains very few NFT,
they are always confined to the hippocampus, the nucleus basalis Meynert, the
amygdala and the entorhinal-transentorhinal area. This stage of NFT
distribution may be associated with mild cognitive impairment (MCI), senescent
forgetfulness and preclinical AD. Only after reaching high densities within
limbic, paralimbic and inferotemporal areas, do NFT emerge in prefrontal,
parietotemporal association areas involved in the neural control of language,
attention and perception. The neuropathological criterion for a definitive diagnosis
of AD is reached only when NFT clusters emerge in association neocortex
(ADRDA-NIA criteria; Alzheimer’s Disease and Related Disorders
Association-National Institute on Aging, 1997).
Normally tau
binding to microtubules stabilize the axonal cytoskeleton. Phosphorylated tau
cannot stick to microtubules. Tau –when differentially posphorylated –promotes
the assembly, disassembly, and reassembly of microtubules, as needed by the
cell. Apo-E3 (see below), by sticking to tau, may help keep phosphates away, while
Apo-E4 fails to do so. This failure leads to a gradual accumulation of tau
proteins with phosphates. These phosphates can cause tau to leave its post at
the microtubule prematurely. Then, because tau dislikes the cell's watery
environment, it may intertwine with another tau molecule to form paired helical
filament. These filaments congregate to create NFT. The hyperphosphorylation of
tau is achieved by the deregulation of the cell-cycle kinase Cdk5
(cyclin-dependent kinase 5). The physiological function of Cdk5 is not quite
clear, it maybe involved in the regulation of actin cytoskeleteon, modulate
signaling cascade (DARP32), control axonal transport, etc.
Plaques (Plate) have a central core of amyloid protein
surrounded by astrocytes, microglia an dystrophic neuritis containing paired
helical filaments. These spherical foci, containing enlarged argentophilic
axons/synaptic terminals/dendrites associated with extracellular amyloid
are thought to represent sites of abnormal synaptic interactions. In AD and in
aged primates, neurites in plaques are derived from a variety of transmitter
systems, including cholinergic, catecholaminergic, and peptidergic neurons. Extracellular
amyloid fibrils, the proteins of which are arranged in a predominantly
beta-pleated sheet configuration, are important components of plaques.
While most senile plaques are of the 'diffuse' type (not associated with
altered neurites and reactive glia), some amyloid deposits in association
cortices and limbic structures are much more fibrillar and compacted, with
surrounding neuritic alterations together with activated microglia and
astrocytes (these are the so called classical or neuritic or senile plaques=NP,
or SP).
Amyloid β deposits (A β) are found in brains of both
mentally intact aged and AD individuals with the same and relatively uniform
patterns of distribution in both groups. The amyloid core of plaques can
contain multiple species of amyloid B-proteins, including a form ending at
amino acid 42 that is prone to aggregation (A β 42) and a slightly shorter
species (A β 40) that is normally produced. Brains from patients with AD
post mortem are characterized by an anatomically widespread process of amyloid
deposition and senile plaque formation (also called neuritic or amyloid plaques).
Neuritic plaque densities are highest in the temporal and occipital lobes and
lowest in the frontal and limbic cortex. According to recent studies the
plaques and their topographical and temporal time tables are independent of the
tangle development (Wisniewski, 1996). A correlation between amyloid
accumulation and dementia has been debated. A β can exist in various forms
as monomers, dimmers, oligomers and highly compacted admixtures of fibrils and
smaller aggregates (amyloid plaques).
In addition to the two classical
histopathological features, the brains of patients with AD also feature a reduction
in synaptic density, loss of neurons and granulovacuolar degeneration in
hippocampal neurons.
3)
Cholinergic deficits, relationship between the cholinergic loss, pathological
lesions of AD and dementia
Loss of basal forebrain cholinergic
neurons. Basal forebrain
corticopetal cholinergic neurons (Plates ) develop tangles, and on the
basis of studies in aged non-human primates, it has been suggested that
cholinergic axons/nerve terminals in cortical target areas form neurites in
some plaques. When these nerve cells degenerate, cholinergic markers (including
presynaptic M2 receptors) are reduced in the amygdala, hippocampus and
neocortex. Loss of these basal forebrain (BF) afferents to the amygdala,
hippocampus (HI) and neocortex may result in decreased activation of target
neurons and thereby, may contribute to some of the clinical manifestations of
dementia.
Most studies show the presence of a very
substantial but regionally variable loss of cortical cholinergic innervation in
AD (Plates ). The severity of this depletion is greatest in the temporal
lobe including its limbic, paralimbic, and association components. Thus, in
advanced stages of the disease, temporal association areas (areas 20, 21 and
22) appear almost completely devoid of cholinergic fibers whereas the
entorhinal cortex, hippocampus and basolateral amygdala retain a considerable
residual density of fibres. By contrast the cholinergic fibers in the premotor
cortex, the cingulate gyrus, the sensorimotor cortex, and in some of the frontal
association areas seemed to be relatively well preserved. There is a general
correspondence between the loss of neurons in specific Ch4 sectors and the
depletion of cholinergic innervation in their preferential cortical targets.
For example, there is a greater preservation of the cholinergic innervation of
the cingulate gyrus, which is derived predominantly from Ch4am, when compared
with that of the amygdala, which is derived predominantly from Ch4al. This
corresponds to the fact that Ch4am is less affected than Ch4al. Basal forebrain
cholinergic loss have been reported ranging in magnitude from 30-95% (Plate ),
with a parallel reduction of ChAT activity (30-90%). Many of the remaining Ch4
neurons contain neurofibrillary tangles and shrinkage.
Although the severity of dementia in AD
correlates well with the cholinergic deficit, it has become increasingly
accepted that AD is not primarily a disorder of central cholinergic
neurotransmission, but that the disease involves deficits in multiple
neurotransmitter systems and the impaired cognitive functions result from the
disturbed interactions among multiple transmitter systems. Whether these
profound deficits in cholinergic markers found in end-stage patients are also
found in patients with much earlier disease is controversial. More recent
studies, using the so called ‘unbiased’ stereological counting methods in
patients with mild AD, suggest that there is only a limited loss of BFC neurons
(Gilmor et al., 1999), in the early stages of the disease process (Plate ). Similarly, single-photon emission computed tomography
(SPECT) studies using 123I-idobenzovesamicol (IBVM), an analogue of
vesamicol that binds to the presynaptic vesicular acetylcholine transporter,
suggest that cortical cholinergic terminals undergo only small age-dependent
losses in normal aging, are depleted more in mildly demented AD patients when
disease onset is earlier than age 65 years rather than later, and are not so
devastated in AD as implied by postmortem determination of ChAT activity (50-80%).
Relationship
between the density of plaques and cholinergic fibers. Although some cortical plaques contain
degenerated cholinergic neurites, many plaques contain components from other
neurotransmitter systems, therefore there is no one to one relationship between
cortical plaques and degenerating cholinergic fibers in AD
Relationship
between cortical cholinergic fibers and density of cortical tangles. There is a modest correlation between
tangle density and percentage of cholinergic fiber loss. However, there are
also discrepancies. For example, the auditory association cortex and the
anterior cingulate gyrus contained an almost identical density of tangles,
while the former displayed a much greater degree of cholinergic fiber loss.
Relationship
between plaques and tangles and loss of BFC neurons. There is a correlation between Ch4
neuronal loss and plaques in anatomically related as compared with unrelated
cortical sites (Arendt et al., 1987). Some presumably related cortical areas,
however, showed little correlation with Ch4 loss. There is thus only partial
support for the contention that cortical plaques by themselves cause retrograde
degeneration of Ch1-Ch4 neurons or that pathologically altered Ch1-Ch4 neurons
are responsible for the anterograde deposition of cortical plaques. There is no
correlation between cell loss in Ch4 sector and the density of tangles in
anatomically corresponding cortical areas.
4) Other neuropathological-neurochemical
abnormalities
Loss of striatal cholinergic neurons. There is no significant change in the
neuronal number or perikaryal size of the cholinergic neurons of the dorsal
striatum in AD. In contrast, there is a significant loss (74%) of the
cholinergic neurons in the ventral striatum (Lehericy et al., 1989).
A cholinergic denervation within the
dorsomedial thalamic nucleus has also been reported (Brandel et al.,
1991).
Loss of brainstem neurons. A small number of mesopontine (Ch5 and
Ch6 according to the nomenclature of Mesulam) cholinergic neurons of the brain
stem in AD have been shown to contain neurofibrillary tangles (German et al.,
1987; Mufson et al., 1988). In contrast to the BFC, however, these brainstem
cholinergic groups show almost no neuronal loss in AD (Woolf et al., 1989). In some patients, reductions occur in
numbers of neurons in the noradrenergic locus coeruleus (LC) and in
noradrenergic cortical markers. The
average loss of neurons of the LC in AD has been found to be either similar or
greater than the average loss of Ch4 neurons. On the basis of cortical ChAT
(choline acetyltransferase, the enzyme responsible for the acetylcholine
syntesis) activity and LC neuronal loss, Wilcock and coworkers (1988) divided
their AD patients into two groups. In a small subgroup, cortical ChAT activity
was close to normal, while LC displayed a marked cellular loss. In the majority
of AD cases a substantial loss was observed in cortical ChAT activity, while LC
displayed a smaller degree of loss. Neuronal loss in LC has been found to be of
greater magnitude within the dorsal aspects of this nucleus, which projects to
the cerebral cortex, than within the ventral LC, which projecs to subcortical
regions (Marcyniuk et al., 1986). Serotoninergic neurons of the raphe
complex may also be affected.
The majority of investigators, report a greater loss of cortical cholinergic
(50-80%) as compared with serotoninergic (40-50%) or noradrenergic (30%)
innervation. The Ch4 cholinergic neurons display a larger and more consistent
loss of neurons (30-95%) in AD when compared with the reported losses in the
dopaminergic neurons of the mesencephalon (0-43%), the serotoninergic neurons
of the raphe (0-39%) or the histaminergic neurons of the hypothalamus.
Amygdala. Neurofibrillary tangles, senile
plaques, and neuronal loss occur in the amygdala and somatostatinergic neurons
are one of the affected cell populations. These lesions of the amygdala may
contribute to some of the emotional, motivational, and associative
abnormalities occuring in patients with AD.
Hippocampus and associated circuits. Neurofibrillary tangles are common in
hippocampus and associated regions, with hippocampal pyramidal neurons
particularly showing evidence of several types of structural pathology, e.g.
Hirano bodies, granulovacuolar degeneration, changes in dendritic arbors. NFT
also occur in neurons of the subiculum and layer II of the entorhinal
cortex. In addition, plaques are common
in these regions, and a variety of transmitter systems have been implicated in
the formation of neurites. Excitatory amino acids may be important transmitters
in some at-risk circuits in these regions. Lesions of these hippocampal systems
are thought to be important in the genesis of some of the memory deficits
occuring in AD.
The tables in Plate summarizes quantitative data showing cell loss
in hippocampus in aging and AD. Plate shows NFT tangles in layer II of the
entorhinal cortex, the cells of origin of the major component of the perforant
pathway that links the entorhinal cortex with the hippocampus. The lower
photomicrograph of this plate shows with Alz50 antibody the degenerating
terminals of the perforant pathway in the dentate gyrus.
Neocortex. The neocortex consistently shows
tangles, plaques and reductions in numbers of neurons. Intrinsic
somatostatinergic neurons develop tangles; their processes participate in the
formation of plaques and counts of senile plaques correlate with reductions in
levels of somatostatin (SS-like) IR. Reductions occur in SS, glutamate and M2
binding sites in AD cortex. More recent studies suggest that levels of CRF, a
peptide present in some cortical neurons decreased and there is a reciprocal
increase in CRF receptors. Plate 31 shows that NFTs are especially
abundant in sensory association regions (like Brodmann’s area 21-22), but much
more sparse in primary sensory regions such as the primary auditory cortex
(Brodmann;s area 41-42.)
5)
Progression of the disease. The primary target
The stereotypic involvement of specific
neuronal populations and relative sparing of nearby or intermingled neurons in
a number of system degenerations, including AD, Parkinson’s disease and other
dementias suggests that progression of these diseases may involve transneuronal
degeneration. In other words, irrespective of the primary causal factor, once a
population of neurons has been destroyed, transneuronal degeneration of their
input and target neurons is likely to contribute to the final pathological
picture. The pattern of cell loss is dictated by connectivity. Studies
comparing the location of NFTs and SPs in the neocortex or in the entorhinal-dentate pathway and the
hierarchical progression from the transentorhinal area, involving secondarily
the hippocampus, and finally reaching the neocortex indeed suggest such a
scenario (Braak and Braak). However, the successive involvement of cortical
areas is not due to the simple spreading of the lesion from one area to its
neighbor. A spared area may be located close to a severely affected one, that
should have been lesioned if pathology had progresses by contiguity.
Virtually all the cell types lost in AD
are known to be connected directly to tangle-rich regions of the association
and limbic cortices or are themselves located within these regions. Ventrally
located neurons in the LC that project to spinal cord are spared at the expense
of dorsally and centrally located cortically projecting neurons. Within,
cortically projecting cells, those with connections with frontal and temporal
regions are more severely damaged than those with occipital connections.
Dopaminergic neurons of the substantia nigra, projecting to the corpus
striatum, are essentially undamaged in comparison with neighboring cortically
projecting VTA neurons. Neurons of the midline thalamus projecting to the
frontal cortex are damaged, whereas those of the dorsal and lateral nuclei
which project to the tangle-free somatosensory cortex, are preserved. Finally,
a greater loss of neurons from the nucleus basalis is seen in those regions
projecting to the temporal cortex, where tangle densities are highest.
Therefore, the cortex, especially the temporal lobe may be the initial site
of the lesion with AD. This is strengthened by "longitudinal"
studies of patients with Down syndrome in whom plaque development, tangles and
particularly a deposition of B-amyloid protein are the earliest pathological
changes found in the amygdala and hippocampus. It is proposed that changes
within pathways bounded by the hippocampus and the amygdala later "spread
out" by way of corticocortical or subcortical connections to involve the neocortex and areas such as
the nucleus basalis and LC (Mann et al). Longitudinal MRI study (Fox et al.,
1996) of asymptomatic individuals at risk of autosomal dominant familial AD
cases suggest that hippocampal atrophy developes in these subjects before the
appearance of symptoms.
Perry et al. (1981) have provided
indirect evidence indicating that the loss of cortical cholinergic
innervation in AD occurs earlier than the loss of other neurotransmitter
systems. Studying temporal neocortex, these investigators divided their
cases into neuropathologically mild, moderate, and advanced groups on the basis
of cortical plaque counts. In the mild group, only ChAT activity was
significantly reduced but other markers were normal. In the moderate group, in
addition to ChAT loss, losses in DBH (dopamine-beta-hydroxylase, the enzyme
synthesizing noradrenaline) and GAD (glutamic acid decarboxylase, the
synthesing enzyme for GABA) and an increase in substance P (SP) were found.
Finally, in the severe group, an additional decrease was observed in cholecystokinin
(CCK). Biopsy samples of the frontal lobe obtained within a year of the
appearance of clinical symptoms have been shown to display up to a 95%
reduction of ChAT activity (Bowen et al., 1982), providing further indication
that the cholinergic denervation appears quite early in the course of AD.
Recent studies with transgenic animals
tend to support the idea that the initial target in AD may be the synapses.
Several electrophysiological studies of young mice transgenic for human APP
with AD causing mutations have revealed significant deficits in basal synaptic
transmission and/or LTP in the hippocampus well before the development of
microscopically detectable BA deposits or plaque formation (for ref. see Hardy
and Selkoe, 2002). This ‘synaptosis’ would be consistent with findings over the
years that patient’s degree of dementia is more highly correlated with the loss
of nerve terminals in their brain than with other pathological features, such
as plaques or tangles, degree of neuronal loss or extent of gliosis (Terry et
al., 1991). Interestingly, in some APP transgenic mouse lines, the number of
synaptophysin-positive presynaptic terminals are 30% less than in
non-transgenic controls at age 2-3 months, as there soluble BA levels rise, but
before BA plaque formation begins (Hsia
et al., 1999). This animal work fits nicely with growing evidence that memory
and cognitive deficits in MCI and AD patients correlate best with the soluble
pool of cortical BA (Lu et al., 1999). It is particularly encouraging that
single systematic injection of an antibody to BA into 22 month-old APP
transgenic mice (Dodart et al., 2002; Kotiinek et al., 2002) reversed the
memory-deficits in the absence of any change in the overall levels of BA
deposits. Work with cultured brain neurons by Cotman and his colleagues also
suggest that terminals may undergo a caspase-dependent degeneration without
necessarily killing the entire nerve cells, at least not immediately. Ultimately, as nerve cell loses more and more
of its terminals, it will die, because it needs trophic factors (see later),
produced by other neurons with which it connects, to survive. Thus there is a
long period of neuronal dysfunction that may contribute to cognitive decline
before there is frank neuronal loss. Such slow neuronal degeneration may not be
considered classic apoptosis.
6)
Pathology of the aging brain in relation to AD
The distribution of NFT and SP are
independent from each other. Whereas neocortical NFT and neuritic plaques are
usually absent in most mentally intact aged persons, BA deposits increase with
age and affect up to 80%. BA and diffuse SP in the absence of neuritic
pathology appear to be part of normal aging with no clinical significance.
Whereas neuritic lesions in neocortex may be absent in 8-36% of demented
individuals over age 75, most of them showing large number of NFT in the hippocampus.
Using both histochemical and biochemical
methods, an age-related loss of cholinergic innervation of the hippocampus
(50%) and entorhinal cortex (35%) has been reported, which became established
after 80 years of age (Perry et al., 1992). Thus, there seems to be an age
related depletion of cortical cholinergic innervation, but that it emerges late
in life and is quite modest when compared to the magnitude of the loss in AD.
There are, however, some similarities to the anatomical pattern seen in AD in
that the cholinergic innervation of the cingulate gyrus appear to be spared and
that of the temporal cortex affected most severely. Investigations of age-related
changes in the cholinergic neurons of the basal forebrain have produced
inconsistent results. While some studies found no age-related change in the
number of Ch4 neurons, others report a 30-70% decrease in number and shrinkage
of nucleolar volume, but not until the ninth decade of life (Lacalle et al.,
1991). Individuals older than 60 years had an average 20% decrease in
presynaptic terminals in the frontal cortex compared with individuals younger
than 60 years. (Masliah, Terry).
It may be difficult to differentiate with
any certainty, autopsy cases of early AD from mentally intact aged subjects and
to determine whether the density and distribution of BA, SP and NFT in
nondemented elderly are related to the normal aging process or to incipient AD.
Apparently BA begins around 30 years before manifestation of cognitive
deficits. At present, the borders between normative aging and AD are not clear,
and the etiology of changes in the aging brain awaits further elucidation.
Minimum cognitive impairment (MCI) is characterized by abnormal memory in
patients who have otherwise preserved intellectual function and no disturbance
of activities of daily living. MCI represent a transitional state between
normal aging and AD.
7a)
Clinical-pathological correlations. General
Impairment in memory may result, in part
from a combination of lesions: deafferentation of the amygdala and hippocampus;
pathology intrinsic to hippocampus; and abnormalities of circuits linking
hippocampus to neocortex. Focal cortical signs (e.g., language abnormalities or
visuospatial impairments) may be attributed to deafferentation of specific
neocortical regions by brainstem and basal forebrain lesions admixed with
intrinsic cortical pathology. Defects in judgement may be attributable to
lesions in frontal cortex, while abnormalities in amygdala may contribute to
some of the emotional problems occuring in these patients.
The association between cerebral plaques
and tangles, on one hand, and presenile dementia, on the other hand, was first
suggested by Alzheimer in 1907. In 1968, Blessed and colleagues provided the
first regression analysis between counts of neocortical plaques and
psychometric tests, showing a strong correlation. When examined closely,
however, the data used in their analyses reveal that many patients on their
charts were either demented without plaques, that is did not have
histologically diagnosed AD, or were not demented with relatively few plaques
and again were not classifiable as having AD. Without those patients not having
AD, their data points do not provide a strong correlation on reexamination
(Terry et al., 1991). The modest correlation between tangle density and
cognitive loss lends to support to the notion that although tangles are valuable
markers of the disease and are probable major contributors to
hippocampal-entorhinal malfunction, they are only minor players in neorcortical
deficiency. On the other hand, recent studies of the
AD dissect human memory into distinct
compartments (G. van Hoesen). One of the earliest changes in AD occurs in the
hippocampus, particularly its subicular component. Other changes early in the
illness affect the anterior parahippocampal cortices such as the entorhinal
cortex. These lesions disconnect the hippocampal formation from the association
cortices and probably underlie the early signs of AD such as changes in the
anterograde compartments of the episodic (contextual) memory. Later changes
affect the lateral temporal, posterior parahippocampal, temporopolar and
anterior insular cortices further exacerbate the problem and contribute to
retrograde memory abnormalities in the contextual realms. The involvement of
the multimodal association cortices would seem to mark the point in AD when
generic (semantic) memory decline, language, abstract reasoning are lost and
where even self-identity is lost.
7b)
Neuropsychiatric symptoms/clinical –autopsy findings/ involved neural networks
Apathy,
depression, agitation. Apathy
is among the most common symptoms of AD. Apathy is characterized by a lack of
interest in usual activities, hobbies, loss of interest in social; engagements,
etc. Depression: inability to experience pleasure and manifested by sadness,
feeling of worthlessness, etc. Agitation: excessive motor activity associated
with a feeling of inner tension.
Studies with SPECT and
PET revealed diminished cerebral blood flow in the anterior cingulate regions
in patients with AD and prominent apathy (Craig et al., 1996; Migneco et al.,
2001). Histopathological studies have identified relationships between
agitation and NFTs in the frontal lobe (Tekin et al., 2001), cholinergic
deficits (Minger et al., 2000) and cell loss in the rostral locus coeruleus
(Matthews et al., 2002). Also, neuroimaging reveals disproportionally reduced
cerebral blood flow in frontal, temporal and parietal regions in patients with
aggression and agitation (Hirono et al., 2000) and depression (Minger et al.,
2000; Hirono et al., 1998; Starkstein et al., 1995). Quantitative EEG studies
reveal increased slow wave posterior activity in patients with AD and
depression compared with patients without depressive mood changes (Pozzi et
al., 1993).
Psychosis. Is represented in AD by the occurrence
of delusions or hallucinations that have their onset after the appearance of
the dementia syndrome and are not attributable to some other psychotic disorder
or to a substance-induced disorder.
Most quantitative EEG
studies have found slowing in patients with psychosis compared with those
without delusions and hallucinations (Edwards et al., 2000). Studies using
SPECT have identified differences between AD patients with and without
delusions. Mega et al. (2000) found lower perfusion in right and left
dorsolateral prefrontal, left anterior cingulate and left ventral striatal
regions. There were also reductions in the left pulvinar and the dorsolateral
parietal cortex bilatereally. Psychosis has been associated with increases in
SP in the medial temporal prosubiculum area and NFTs in the middle frontal
cortex and with diminished neuron counts in the parahippocampal region of the
medial temporal lobe (Forstl et al., 1994). An increase in M2 muscarinic cholinergic
receptors is present in the frontal and temporal cortex of patients with AD and
psychosis. The increased abundance of these receptors suggests that they have
been upregulated in response to the degenerating presynaptic cholinergic system
(Lai et al., 2001). This change may provide a basis for the utility of
cholinomimetic compounds in the treatment of behavioral disturbances in AD
(Cunningham, 2004).
Neural
circuits. The pattern of
distribution of neuronal and transmitter changes leads to dysfunction of neuronal
systems. Two neural networks have been recognized as particularly important to
the mediation of neruopsychiatric disturbances: the limbic system and the
fronto-subcortical circuits. The limbic system is responsible for assigning the
valence of emotional value to human experiences. The limbic system includes
both cortical and subcortical structures integrated into a functionally related
circuitry involved in emotional processing of sensory stimuli. Cortical regions
included in the limbic system are: hippocampal formation, anterior hippocampal
gyrys, cingulate gyrus, subcallosal cortical regions, temporal pole, insula and
posterior orbitofrontal cortex. Subcortical structures include the amygdala,
septal area and substantia inniominata. Five frontal-subcortical circuits
linking frontal lobe regions to subcortical structures and back to the frontal
lobe have been described (Alexander et al., 1986). Frontal-subcortical circuits
mediate executive function (dorsolateral prefrontal-subcortical circuits),
motivation (medial prefrontal-anterior cingulated-subcortical), and control of
behavior in social contexts (orbitofrontal-subcortical) as well as motor and
eye movement functions.
8) Etiology and genetics of AD
In the last ten years good progress has
been made in elucidating the resulting changes of single-gene defects in
familial forms of AD. Several highly penetrant genes have been cloned for rare,
autosomal-dominant, early onset froms of AD. Plate summarizes the major
gene defects, including mutations in the amyloid precursor protein and
presenilins that lead to increased amyloid deposit and AD. The strategy has
been to search for mutations in identified genes in the rare familial forms of
the disease, in the hope that this might provide some insight into the much
more common sporadic cases of the disease. Unfortunately, these gene defects
affect only about 1% of all AD cases, however, several risk factors (ApoE4 and
Alfa2 macroglobulin polymorphism) have also been discovered that results in AD
in the non-familial form of the disease. It is assumed that in the late-onset
forms of AD there may be multiple genes, each with alleles that are common in
the general population, they have relatively weak effects on their own, they
may produce more than one effect and they may interact with each other (Kennedy
et al., 2003).
Amyloid deposits, composed of a 4kD BA (beta amyloid)
protein derived from the amyloid precursor protein (APP). APP is a
single transmembrane domain (TM) protein with multiple alternate transcripts, which
are expressed ubiquitously and present in dendrites, cell bodies and axons. APP
is coded by a gene located on the long arm of human chromosome 21. APP
exists in three isoforms, 695, 751 and 770 amino acids. APP is synthesized in
RER, glycosylated in the Golgi apparatus and delivered to cell surfaces as an
integral membrane protein. Cell culture studies have implicated APP in having
roles in cell survival, neurite outgrowth, neuroprotection, cell-substrate
interactions, modulating LTP. Two isoforms (751 and 770) contain a domain that
can act as a serine protease inhibitor (Plate ).
The normal metabolic processing of APP by
three proteases generates both amyloidogenic and non-amyloidogenic products. An
alfa-secretase acts at residue 612, within the BA sequence, to produce
non-amyloidogenic, intramembranous 10-11kDa C-terminus product (p3=alfa-stub)
and a secreted APP fragment (sAPP). The Beta
secretase (BACE) cleaves at residue 597 to release a truncutaed sAPP and a
membrane-associated, 8-12 kDa C-terminus fragment (CT or beta-stub), containing
the whole sequence BA. The gamma
secretase cleaves at various sites presumed to be integrated in the cell
membrane to produce an extracellular BA fragment of 39-43 amino acids. (see for
explanation Plates ). The larger BA42 peptides are more prone to
self-aggregate and are thought to be more pathogenic.
The gamma secretase is a complex
includes the presenilins, (Ps1 and PS2) and three other proteins
(nicastrin=NCSTN; APH1A and PEN2).
The beta amyloid is implicated in the
genesis of AD because all mutations that have been shown in AD increase BA42
deposit (Plates ). The BA peptide contains 14 amino acids of the
transmembrane domain and 28 amino acids of the adjacent extracellular domain of
APP. Amyloidogenesis could result from a variety of mechanisms, including gene
mutations (716, 717, 692, 670/671), gene dosage, altered levels of APP
transcripts/isoforms, and abnormalities of post-translational processing. The
mutation of the APP gene is a rare cause of AD (6-7 families in the world!).
Transgenic mice that overexpress the mutant human APP 695 gene, develop typical
plaques as well as difficulties in learning at older age (Hsiao et al., 1996),
suggesting that the increased production of BA may be especially prone to formation
of plaques. These data seem to confirm the amyloid-cascade hypothesis of Hardy
(see below). BA is toxic to neurons in culture. Possible means of
toxicity include: 1) disrupting Ca homeostasis (it could form Ca channels
itself or increase membrane permeability); 2) inhibiting axonal sprouting and
LTP; 3) reducing N/K ATPase activity; 4) altering redox potential; 5)
interacting with p75 neurotrophin receptors; 6) disrupting mAChR coupling to
G-proteins; 7) impairing glucose and glutamate transport (see Plate for a schematic summary for B-APP
metabolite-induced cellular toxicity).
_________________________________________________________________________________________
The Presenilins. The presenilin genes (PS1 and PS2) are
two homologous genes encoding polytopic 8 transmembrane proteins. The gene for
PS1 was identified using a positional cloning strategy that led to the
identification of missense mutation in a gene on chromosome 14 which encodes a
43-kDa protein (Sherrington et al., 1995). PS2 was identified on chromosome 1
on the basis of its homology with PS1; it encodes a 50-kDa protein. The
sequence of both proteins predicts the existence of 8 TM domains that share
more than 60% amino acid identity (Plates ). Like APP, they appear to be
expressed ubiquitously. Although, interestingly, in human PS-2 is primarily
localized in the dentate and hippocampal granule cells and in the deep layers
in the frontal and temporal cortices. So far, more than 35 mutations, mainly
involving the conserved TM domains or a region adjacent to a large
intracytoplasmic loop, have been identified. All but one are missense mutations
that appear to have a toxic gain-of-function effect (Hardy, 1997). Presenilin
mutations cause an increase in the production of BA42 of about 2-3-fold.
Mutations in the presenilin gene are thought to account for about 20-25% of all
familial AD cases. Presenilin is cleaved to produce an N-terminal (28kDa) and C
terminal (18kDa) fragment thought to be an endoproteolytic cleavage. Only the
cleaved protein is functional, uncleaved form is degraded through the
proteosome. Presenilin proteins have been localized to the smooth and rough ER
and the Golgi.
The function of the presenilins has been
clarified unexpectedly by the finding in the C. elegans of a protein (Sel-12), with considerable homology to the
presenilins. Sel-12 has been shown to be involved in the Notch signaling
pathway. The Notch pathway is an evolutionary conserved cell-cell signaling
mechanism involved in cell fate decisions during different cellular and
developmental processes, including neural development. In vitro studies of
neurons from mouse cerebral cortex revealed that the formation of neuronal
contacts results in activation of Notch receptors, leading to restriction of
neuronal growth and a subsequent arrest in maturity (Sestan et al., 1999). A
critical step in Notch signaling involves intramembraneous cleavage of
the protein to liberate the Notch intracellular domain (ICD) and the
translocation of the ICD to the nucleus where it functions as a transcriptional
coactivator.
Because
mutations in Sel-12 can be rescued by the introduction of normal human PS1 or
PS2, it seems likely that the presenilins serve the same signaling function in
humans. The finding that the null mutations in the Drosophila melanogaster presenilin gene abolish notch signaling and
nuclear translocation (Struhl and Greenwald, 1999) serves to emphasize this
point. The deletion of PS 1 in mice greatly reduces gamma secretase
activity and increases the accumulation of the alfa-stubs and Beta-stubs, the
substrates for gamma secretase. This finding and the existence of two conserved
aspartates in the presenilin protein (marked D257 and D385 in TM6 and TM7
domains) that are required for the gamma secretase cleavage of APP and the
generation of the Notch intracellular domain, has led Selkoe and his colleagues
to suggest that PS1 (AND PS2) are components of the the long-sought-after gamma
secretase (Aguzzi and Haass, 2003). These studies show, that presenilins
regulate both APP processing and Notch signaling by influencing unusual
(intramembraneous) protein cleavage events (Plate). The variants of the
genes for either of the presenilins change the function of the gamma secretase
in a way that somehow leads to increased accumulation of BA.
Mutations
in PS1 and PS2 alter the way that cells handle APP processing. APP is folded
and processed in the endoplasmic reticulum and Golgi for transport to the cell
interior. PS1 allows misfolded APP to accumulate. Misfolding, in turn, might be
what causes APP to be cut in the wrong place, releasing extra BA42. A selective
and highly significant increase of BA42 occurs in the plasma and in media from
cultured skin fibroblasts of patients with PS mutations. PS1 knocked out mice
showed a dramatic defect in the somites (Sisodia et al). Transgenic mice
expressing mutant PS1 also show increased BA42 levels in brain. Finally, direct
analysis of the patients bearing PS1 mutations demonstrates a significant
increase in the density of BA42-containing plaques compared to that found in
patients with sporadic AD. The idea that all known genetic mutations causing
familial AD are found either in the substrate (APP), or in the proteinase
(PS1-gamma secretase), which are the rate-limiting proteins in the production
of the amyloid peptide, is intellectually very appealing. According to Wolozin et al (1996), PS2
mutation induce apoptosis in cultured nerve cells under conditions in
which normal PS2 had no effect. The accelerated rate of neuronal cell death that
occurs in AD may therefore result from the additive effects of aging, activated
apoptosis and BA toxicity.
Interestingly,
not all mutations in PS1 lead to dementia via changes in BA production. In one
recently reported PS1 mutation (Gly183Val) was associated with Pick’s disease
(frontal lobe dementia with taupathy) in the absence of amyloid plaques
(Dermaut et al., 2004)
It
is interesting to note that a double transgenic mice that overexpress mutated
PS1 and APP genes showed deficits in the number of cholinergic synapses in the
frontal cortex, implying diminished function of the cholinergic system.
Nonetheless, no significant changes in the basal forebrain cholinergic neurons
were noticed in these transgenic animals (Wong et al., 1999). Also, no changes
in the cholinergic innervation of the entorhinal cortex was noticed – a
cortical region that is prominently affected in AD. Interestingly, Kim found
that the p75 neurotrophin receptor, that is specifically expressed in basal
forebrain cholinergic (BFC) neurons and has been implicated in the regulation
of cell survival and death, is a gamma-secretase substrate. This may be the
molecular basis for selective degeneration of BFC neurons in AD.
.
Apo-E4. The gene encodes apolipoprotein E, a protein that binds to
cholesterol, which among other functions, transport lipid (cholesterol) between
cells. The gene is localized on chromosome 19. The common isoforms of apo-E are
encoded by three Apo-alleles, E2, E3 and E4, which differ from one another as a
result of amino acid substitutions at two specific codons. The apo-E4 allele is
associated with a threefold increase of the risk for AD, meaning that
heterozygotes are three times more likely to develop AD, than people carrying
alleles for other isoforms of apo-E (Roses group from
______________________________________________________________________________________
Alfa2macroglobulin binds to the same LRP (low-density
lipoprotein receptor-related protein) receptor as apo-E4 and could prevent the
formation of the insoluble B amyloid fibrils that are considered most toxic to
neurons. Some people carrying apo-E4, even those with two copies, appear not to
get AD in the presence of the ‘good’ alfa2M gene.
Cholesterol homeostasis. Karen Duff and coworkers at Nathan
Kline Institute in NY have shown that cholesterol is a major risk factor in
amyloid accumulation and that pharmacological and genetic manipulation of
cholesterol synthesis impacts the generation, transport or clearance of BA
peptides (Refolo et al., 2001). Although in clinical AD cases, serum
cholesterol level does not correlate with the disease, recent epidemiological
studies showed that treatment with cholesterol-lowering statins lowered the
risk of developing AD (Wolozin et al., 2000). In experimental animals, reduced
cholesterol levels results in reduced B and gamma-secretase activity, and
increased alfa-secretase activity, consequently reducing BA levels. Cholesterol
bound to apo-E containg lipoprotein particles are secreted by astrocytes and
taken up by neurons where they affect signal transduction through low density
lipoprotein-related protein (LRP). Cholesterol binds also to several synaptic
proteins and is necessary for the formation of synaptic vesicles and for the
clustering of certain postsynaptic receptors. The LRP receptor related protein
has been directly implicated in synaptic plasticity in hippocampal slices (Zhuo
et al., 2000) and the apoE4 isoform is less able to promote neurite outgrowth
than other apo-E isoforms (Nathan et al., 1994). (Plates ) New findings suggest a positive feedback in
the sense that increased production of BA exacerbates lipid abnormalities.
Increasing evidence suggests that LRP mediates the efflux
of BA from the brain to the periphery. LRP is a
multifunctional signaling and scavenger receptor that can bind a variety
of ligands including apoE, alfa2M and APP. LRP antagonists have been shown to
reduce the efflux of BA from the brain
by 90%. Cerebral amyloid load was doubled in LRP knockout mice. BA bound to LRP
are internalized to endosomes, and are then either delivered to lysosomes,
where they are degraded or undergo transcytosis across the blood brain barrier
into the plasma. Several other protease enzymes, including IDE (insulin
degrading enzyme), NEP (nephrilysin), PLG (plasminogen) are important in BA
degradation. The gene for IDE is located on chromosome 10, the NEP on
chromosome 3, PLG on chromosome 6 (see Plate by Tanzi and Bertram, 2005).
The role of inflammatory molecules
in the pathological process of AD is not fully understood, but they may be
involved in a number of key steps in the pathological cascade. It has been
shown that IL-1 (and possibly IL-6) can regulate APP synthesis. The promoter of
the gene encoding APP contains both heat-shock and interleukin-responsive
elements, and IL-1 expression is rapidly induced following brain injury and
other pathogenic insults. This may trigger enhanced APP synthesis and BA42
deposition and set up a vicious cycle whereby amyloid deposits stimulate
further cytokine production by microglia, leading to even higher expression of
APP. While transient glial activation is beneficial as part of the organism’s
homeostasis response to injury, abnormal glial activation results in a
detrimental neuroinflammatory cycle. Activated microglial cells produce and
release potential toxic products, including cytokines, proteases and free
radicals, which could damage neuronal cells by 'bystander lysis'. For this
reason, activated microglial cells might be the link between BA4 amyloid
deposition and neuronal degeneration. It is possible that treatment with
certain anti-inflammatory drugs may reduce the release of toxic factors
produced by activated microglial cells but, at the same time, they might also
affect the rate of aggregation of the BA4 peptide by shifting the balance
between factors that promote and those that prevent aggregation. In fact,
studies have shown that cyclooxygenase (COX)-2, an enzyme involved in
inflammatory mechanisms as well as neuronal activities, is up-regulated in AD.
Transgenic mice expressing both the human APP mutation (APPswe) and the human
presenilin (PS1-A246E) mutation, with resultant AD type pathology, were crossed
with transgenic mice expressing human (h)COX-2 in neurons. At 24 months of age
the triple transgenic mice showed a >2 fold elevation of BA immunopositive
plaques in frontal cortex and hippocampus, compared to APPswe/PS1-A246E double
transgenics (Pasinetti, 2002).
9)
Transgenic mice models
It is currently uncertain how the synaptic degeneration observed in the APP and PSAPP relates to the process of neurodegeneration in human AD, and whether this synaptic loss could be a precursor of neuronal cell death given longer time periods than are possible in a mouse. However, it is clear, from the absence of neuronal loss in APP and PSAPP models, that physiological Aβ accumulation and amyloid plaque formation do not cause rapid neuronal cell death in vivo. This in turn suggests that Aβ species are unlikely to cause widespread neuronal loss in the absence of secondary pathological events in human patients. This is consistent with human neuropathological studies that show no correlation between overall levels of amyloid deposition and clinical progression of AD.
The mechanism of neuronal cell death in mouse models that develop NFT pathology is uncertain, but most of the data suggest that apoptosis is not the primary mechanism of neuronal cell death. Recent studies in mice expressing mutant MAPT transgenes have implicated axonal dysfunction and degeneration as an initiator of MAPT-induced neuronal loss.
Transgenic mouse with amyloid plaques
and NF. Lewis and colleagues (2001) crossed mutant APP and
MAPT (JNPL3) mice, and demonstrated that the double-transgenic TAPP mice
developed enhanced limbic neurofibrillary pathology, when compared with single
transgenic littermates. Importantly, the enhanced NFT pathology in the TAPP
mice was also associated with evidence of neuronal loss in the entorhinal
cortex. Similarly, Gotz et al. (2001) found that the
intracranial administration of Aβ into mutant (P301L) MAPT mice resulted
in the generation of NFTs within the amygdala. Results of these studies
strongly suggested that Aβ accumulation accelerated the development of
neurofibrillary lesions, although the exact mechanism of this interaction was
unknown. Oddo and colleagues (2003) extended these studies by
generating a triple-transgenic model (3×Tg-AD), harboring PSEN1M146V,
APPswe and MAPT (P301L) transgenes. This model accumulates intraneuronal
Aβ, and subequently forms amyloid plaques and MAPT lesions in an
age-dependent fashion. In subsequent studies, Oddo et al. (2004, 2005)
found that Aβ immunotherapy (injection
of anti-Aβ antibodies, or antibodies specific for oligomeric forms of Aβ)
or a gamma-secretase inhibitor in 3×Tg-AD mice led to the rapid clearance of
accumulated Aβ deposition and early MAPT lesions in the cell body. The
removal of both Aβ and MAPT lesions proceeded in a hierarchical,
time-dependent manner; clearance of accumulated Aβ occurred before a
reduction in the MAPT pathology. Furthermore, after clearance of the injected
Aβ antibody, Aβ pathology re-emerged before the appearance of MAPT
lesions. However, later stage hyperphosphorylated MAPT (antibody AT8 and AT180 positive)
lesions were resistant to clearance by Aβ immunotherapy. These
results suggested the existence of reversible and irreversible stages of MAPT
pathology. The nature of this shift from reversible to irreversible
pathological stages is unclear, but one obvious possibility is that MAPT
hyperphosphorylation is associated with aggregation into filaments that renders
the lesion resistant to clearance.
A complete mouse model of AD has proven elusive, probably because of the short lifespan of the mouse and the nature of the relationship between Aβ accumulation and other pathological features that contribute to the complex phenotype of AD. In particular, based on results from APP and PSAPP mice, it seems likely that Aβ accumulation does not lead directly to neuronal cell death in AD but usually requires the initiation of a secondary process. This explanation is consistent with human neuropathological studies that show no correlation between total amyloid deposition and memory loss in AD. By contrast, mice that develop robust MAPT neurofibrillary pathology almost inevitably develop widespread neurodegeneration, regardless of whether the neurofibrillary lesions are generated through expression of a mutant, wild-type MAPT transgenes or over-expression of a relevant MAPT kinase . These results from the transgenic mice clearly confirm the close relationship between MAPT and neurodegeneration and are consistent with human studies that have reported a correlation between NFT pathology and the clinical progression of AD. However, results from TAPP (MAPTP301L×APPswe) and the 3×Tg-AD mouse models support the hypothesis that Aβ accumulation can accelerate, if not initiate, the formation of neurofibrillary pathology . Thus, the transgenic mouse data are consistent with a scheme for AD pathogenesis in which the accumulation of aggregated Aβ oligomers accelerates the parallel process of age-dependent formation of MAPT pathology. However, it is the accumulation of toxic MAPT species (again likely to be early aggregates rather than NFT) or other secondary pathological events (e.g. α-synucleinopathy) that initiates neurodegeneration and, by extension, accounts for most of the clinical syndrome.
10)
Pathogenesis
The
amyloid cascade hypothesis.
Taken together, the available evidence favors a model of the disease in which
diverse gene defects lead to enhanced production, increased aggregation, or
perhaps decreased clearance of BA peptides. These effects allow accumulation
first of the highly self-aggregating BA42 peptide and later the BA40 peptide.
The gradual cerebral buildup of BA in first soluble and then particulate forms
(the microscopically detectable consequence of which is diffuse plaques)
appears to result in local microglial and astrocytic activation, with
concomitant release of cytokines and acute-phase proteins (McGeer and Rogers,
1992; Eikelenboom et al., 1994; Wood, 1997). By means of these inflammatory
changes or by direct BA neurotoxicity, local neurons and their processes can be
injured, causing profound metabolic changes -likely including altered tau phosphorylation
and paired helical filament formation in some plaque associated neurites and in
tangle-bearing cell bodies. Filamentous
BA may alter glia and neurons by causing changes in calcium homeostasis as well
as oxidative injury from free-radical formation. The clinically important
consequences of these various events is synaptic loss and multiple transmitter
deficits. BA depost may trigger caspase activation and apoptosis (Hardy and
Selkoe, 2002).
Critique of the amyloid-cascade
hypothesis. Amyloid
deposit is the central element in the so called amyloid-cascade hypothesis of
Hardy, originally formulated in the late eighties. There are several
problems with this model: 1)
plaques display substantial
interindividual variations and that these variations have no known relationship
to the pattern of cognitive deficits; Against this argument the proponent of
this hypothesis suggest that the degree of dementia in AD correlates much
better with BA assayed biochemically than with histology and the concentration
of soluble BA species; 2) although the initial memory loss
indicates the presence of early limbic dysfunction, the initial plaques tend to
appear in association neocortex rather
than limbic areas. In other words, the NFT distribution patterns that fit
the expected anatomical substrate of the neuropsychological deficit, whereas
the SP do not; 3) extensive
neocortical plaque deposits can be seen in non-demented elderly individuals; 4) the correlation between plaque
density and dementia is usually poor; 5)
The APP/PS1/Alz17 mutant mouse with 30 months of age has massive amyloid
deposits in the cortex, hippocampus and basal forebrain, yet there are no
behavioral deficits and no neuronal degeneration or NFT formation (Holcomb et
al., 1998); 6) Diseases with tau
mutations (on chromosome 17; fronto-temporal dementia=FTD) are associated with
dementia and massive cell loss, however, there is no amyloid deposit or
tangles. This is according to Peter Davies, (known for discovering the
cholinergic deficit of AD in 1976), not an AD mice but an amyloid mice. 7) the neurotoxic species of BA and the
nature of its effects on neuronal function have not been defined in vivo.
However, several lines of evidence suggest that the soluble oligomers of BA,
but not the monomers or insoluble fibrils may be responsible for synaptic
dysfunction, including inhibition of LTP and changes in the density of
synaptophysin (Klyubin et al., 2005). In fact, it is suggested that the large
polymeric aggregates represent inactive reservoirs of species that are in
equilibrium with the smaller putatively neurotoxic assemblies.
Although the amyloid cascade hypothesis
has several weakness, but an alternative hypothesis explaining the cause and
early pathogenesis of AD that has as much experimental support has not emerged.
The scheme in Plate is from D. Price (1998) suggesting that genetic
mutations and risk factors in vulnerable neurons through several
(partially unknown) mechanisms could lead to the clinical syndromes of dementia
and cell death. At present, the mechanisms that underlie the selective vulnerability of these
subsets of neurons are not well understood. However, evidence suggests that
vulnerable cell populations exposed to high plasticity burden (LTP, axonal
sprouting, dendritic remodeling, reactive synaptogenesis) in the adult brain
and the elevated levels of plasticity related cellular activity may increase
the vulnerability to degeneration (Mesulam, 1999). According to this
hypothesis, NFT and SP/AP represent independent by-produts of initially
compensatory but eventually excessive and maladaptive plasticity-related
activity. Old age, genetic mutations, low estrogen, stroke, etc simple
accelerate the temporal course of events that lead to plasticity failure and
therefore lower the age at which the pathological process begins to gather
momentum. The advanced cognitive and
mnemonic activities of the human brain impose a very high plasticity burden.
The identification of factors that
specifically influence the viability and functions of these systems should
allow the design of biological therapies to treat some of the neurological
disorders associated with degeneration of these systems. Plate from
Cuello summarizes in a cartoon most of the known pathogenetic routes that lead
to AD. This cartoon also includes data
showing that increased acetylcholine release in the cortex via M1/M3 receptors
and the inositol-3-phosphate-protein kinase C signaling pathway can lead
enhanced APP levels- a link between cholinergic and APP mechanisms. Plate from a recent review from Isacson et al (2002)
also show the possible relationships between ACh regulation, trophic factors
and BA production. The fact that in the
ancestry of Cherokee Indians the occurrence of AD is lower, and the finding
showing higher rates of AD in Japanese men who emigrated to America as opposed
to those who remained in Japan gives credence to theories that ancestry,
environment, and other factors play additive roles in predisposing a person to
AD.
11)
Therapy in AD
The conclusion that flows from recent
progress in defining the genotype-to-phenotype relationships in familial AD is
a growing consensus that the most effective treatments for AD may be those that
interrupt an obligatory early step, occurring before a progressive cascade of
cell-damaging events.
Currently, the following broad classes of
AD drugs are tested:
1) Protease inhibitors that partially decrease the activities
of the enzymes Beta and gamma-secretase that cleave BA from APP (LY411575;
LY450139 dihydrate; BACE= Beta-site APP-cleaving enzyme; neprilysin as possible
AB-degrading enzyme); there is a concern
that some compounds against gamma secretase might interfere with Notch
signaling and other cell surface receptors
2) Compounds that bind to extracellular AB and prevent
its aggregation into cytotoxic amyloid fibrils. This strategy reasons
that chelation of Cu2+ and Zn2+ may prevent BA deposition. BA deposition was
prevented in APP transgenic mice treated with the antibiotic clioquinol, a Cu2+,
Zn2+ chelator.
3) Immunotherapeutic Approaches. AB maybe considered a self-antigen. It
induces not only local innate immune response but also T-cell activation.
Although T-cell activation can mediate autoimmune disease, this endogeneous
immune response can be beneficial if properly boosted. Parenteral immunization
of APP Tg mice with synthetic AB in complete Freund’s adjuvant can markedly
decrease the number of AB deposits (Schenk et al., 1999). Also, a single,
parenteral administration of a monoclonal antibody to AB has been shown to produced
rapid behavioral improvement. However, passive immunization using monoclonal
antibodies to AB resulted in brain hemorrhage. It was recently shown that
overexpression of TGF-B in the CNS of APP-Tg mice resulted in a significant
reduction of AB-plaque burden by promoting microglial clearance of the peptide.
Adult mouse astrocytes also showed profound capabilities of degrading AB in
vitro and in situ. Thus immune approaches targeted to induce AB antibodies and
immune responses may result in activation of microglia and asytrocytes with a
beneficial effect in AD. The finding that active vaccination wit hAB had
profound AB lowering effects in animal models led to clinical trials in which
an AB1-42 synthetic peptide was administered parenterally with a previously
tested adjuvant to patients with mild to moderate AD. Although the Phase I
study with a small number of patients failed to reveal significant side
effects, a subsequent Phase II trial had to be halted in 2001 (Elan clinical
trial) after about 5% of the patients came down with meningoencephalitis, a
potentially deadly inflammation of the brain and surrounding membrane. In the
postmortem case, there was clear evidence of decreased amount of AB plaques in
the neocortex with marked T-cell infiltration in the CNS, the tangles remained,
however. Despite the adverse effects of
this early human vaccination studies, efforts are in progress to develop more
effective immunization methods.
4) Nonsteroidal anti-inflammatory (NSAIDs) drugs. AB deposits in AD and
mouse models induce immune response including microglial activation, secretion
of proinflammatory cytokines (IL-1B, TNFalfa) and NO. If microglial or
astrocytic activation fails to clear the toxic forms of AB, the innate response
becomes chronic and neurotoxic. In this case, dampening the innate immuno
response may be beneficial, as a number of clinical studies suggest that anti-inflammatory
drugs used in arthritis may delay or slow the progression of AD (Naproxen,
Rofecoxib, Celecoxib, Aspirin, Iboprofen, Indomethacin). Their use, however, can cause considerable
side effects, including gastrointestinal bleeding and perforated ulcers.
5) Statins (Simvastatin, see above at “Cholesterol homeostasis”).
6) Neuroprotective compounds such as antioxidants (vitamin C,
E, ginkgo biloba), MAO inhibitors (selegiline) neuronal calcium channel
blockers, or antiapoptotic agents that interfere with the mechanisms of
BA-triggered putative neurotoxicity.
7) Hormone replacement therapy. Estrogens. Estrogen replacement in postmenopausal
woman decreases the risk of developing AD (Kawas et al., 1997). Estrogen
replacement therapy became lately controversial, especially in the light of
studies showing that hormone replacement therapy may increase the risk for
breast cancer, heart attack and stroke (see recent article in New York Times,
8) Cholinergic replacement therapy and cholinesterase inhibitors are
symptomatic treatments for AD (tacrine, donepezil)
9) Trophic factors (Plate). Recently, a transgenic mouse has been
described that expresses a neutralizing antibody against nerve growth factor
(NGF) (Capsoni et al., 2000). In these mice, brain pathology exhibits
remarkable similarities to the pathology seen in AD, including amyloid plaques,
hyperphosphorylated tau, NFTs in cortical and hippocampal regions and marked
cholinergic neuron degeneration. The anti-NGF transgenic mice show more
pathology that found in transgenic mice that express mutant APP. Cholinergic
neurons and synapses depend on the trophic action of NGF for their function
(ref. in Isacson et al., 2002). The survival effects of neurotrophins in
cholinergic neurons are mediated via high-affinity tyrosine kinase receptors
(trkA). In addition, neurotrophins binds to low-affinity (p75) receptors that
can modify the binding and function of neurotrophins when coexpressed with trk
receptors. The trkA and p75 receptors are synthesized in cholinergic neurons
and NGF is synthesized by the neurons in the target regions and released in an
activity-dependent manner. In individuals with AD, there is typically a marked
loss of trkA receptors in both cholinergic target neurons and basal forebrain
(BF) neurons, which correlates with loss of cholinergic neurons (Mufson et al.,
1997). There are unchanged or increased level NGF levels in the hippocampus and
cerebral cortex, while the levels in the BF are decreased with age-matched
controls. This, together with cholinergic neuron loss and dysfunction, suggests
that NGF is not adequately transported retrogradely to the BF or that binding
to the trkA receptors or release of NGF from hippocampal interneurons, or both,
is compromised in AD and in animal models. Infusion of NGF can prevent
degeneration of axotomized cholinergic septal and BF neurons. APP can augment
the effect of NGF and versus vica. Selective lesions of the cholinergic BF
neurons of rabbits results in BA deposition in cerebral blood vessels and
perivascular neuropil – a pathology seen in a rare familial form of AD. Thus,
there is a close relationships between trophic factors, APP and ACh regulation.
According to recent studies (Moses Chao at NYU, and
10) Environmental
enrichment. Exposure of transgenic mice to an “enriched environment” results in pronounced reductions
in cerebral amyloid deposits, compared to animals raised under “standard
housing” conditions. The enzymatic activity of an of familial AD (FAD)-linked
APP degrading endopeptidase, neprilysin, is elevated in the brains of enriched
mice and inversely correlated with
amyloid burden. Moreover, DNA microarray revealed selective upregulation in
levels of transcripts encoded by genes associated with learning and memory,
vasculogenesis, neurogenesis, cell survival pathways, BA sequestration. These
studies provide evidence that
environmental enrichment leads to
reductions in both the steady-state levels of βA peptides and βA deposition and selective upregulation in
levels of specific transcripts in brains of transgenic mice (Sisodia and
coworkers, 2005). Similarly, studies with elderly suggest that education and
physical exercise can reduce a person’s risk of AD. Although in one study no
correlation was found between education and the formation of plaques and
tangles, but a battery of 19 tests performed periodically in the years before
the donors died revealed that people with high level of education better maintained
their cognitive abilities. The highly educated participants did’t develop AD
until they had about 5x as many plaques and tangles as the less educated
participants (Rush Presbyterian-St. Luke’s Study: News Focus, Science, 309,
864, 2005).