ACT on Alzheimer’s
Alzheimer’s Disease Curriculum
Science of Alzheimer’s
GUIDELINES FOR AND RESTRICTIONS ON USE OF CURRICULUM MODULES
This curriculum was created for faculty across multiple disciplines to use in existing coursework
and/or to develop a stand-alone course in dementia. Due to the fact that not all modules will be
used for all disciplines, topics have been divided into ten modules that can be used alone or in
combination with other modules. Users may reproduce, combine, and/or customize any module
text and accompanying teaching slides to meet course needs. Our only restriction on re-use is
that the modules not be sold in their current or modified form.
NOTE: Recognizing that not all modules will be used with all potential audiences, there is some
duplication across the modules to ensure that key information is contained in each module (e.g.,
screening module is completely duplicated in the diagnosis module because the diagnosis module
is not appropriate for all audiences).
© 2012
Acknowledgement
We gratefully acknowledge our funding organizations, which made development of this
curriculum possible: The Alzheimer’s Association MN/ND Chapter and The Minnesota Area
Geriatric Education Center (MAGEC), which is housed in the University of MN School of Public
Health, and is funded by the Health Resources and Services Administration (HRSA).
We also specially acknowledge the principal drafters of this curriculum module, including
Kathleen Zahs, Ph.D., Maureen Handoko, Ph.D., Hoang Hoa Nguyen, B.S., Samantha Shapiro,
B.A., Katelynn Splett, B.S. and John Reichl
This curriculum is available for use and/or customization by anyone, as long as it is not sold in its
current or modified form.
This project is/was supported by funds from the Bureau of Health Professions (BHPr),
Health Resources and Services Administration (HRSA), Department of Health and Human
Services (DHHS) under Grant Number UB4HP19196 to the Minnesota Area Geriatric
Education Center (MAGEC) for $2,192,192 (7/1/2010—6/30/2015). This information or
content and conclusions are those of the author and should not be construed as the official
position or policy of, nor should any endorsements be inferred by the BHPr, HRSA, DHHS
or the U.S. Government.
Minnesota Area Geriatric Education Center (MAGEC)
Grant #UB4HP19196
Director: Robert L. Kane, MD
Associate Director: Patricia A. Schommer, MA
Overview of Alzheimer’s Disease Curriculum
This module is part of the Alzheimer’s Disease Curriculum developed by ACT on Alzheimer’s.
ACT on Alzheimer’s is a statewide, voluntary collaboration that includes over 50 organizations
and 150 individuals seeking to prepare for the budgetary, social, and personal impacts of
Alzheimer’s disease. All of the modules can be found online at www.ACTonALZ.org
Module I:
Disease Description
Module II:
Demographics
Module III:
Societal Impact
Module IV:
Effective Interactions
Module V:
Cognitive Assessment and the Value of Early Detection
Module VI:
Screening
Module VII:
Disease Diagnosis
Module VIII:
Dementia as an Organizing Principle of Care
Module IX:
Quality Interventions
Module X:
Caregiver Support
Module XI:
Alzheimer’s Disease Research
Module:
Science of Alzheimer’s
Module XII:
Glossary
ACT on Alzheimer's has developed a number of practice tools and resources to assist
providers in their work with patients and clients who have memory concerns and to
support their care partners. Among these tools are a protocol practice tool for cognitive
impairment, a decision support tool for dementia care, a protocol practice tool for mid- to
late-stage dementia, care coordination practice tools, and tips and action steps to share
with a person diagnosed with Alzheimer's. These best practice tools incorporate the
expertise of multiple community stakeholders, including clinical and community-based
service providers:
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•
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Clinical Provider Practice Tool
Electronic Medical Record (EMR) Decision Support Tool
Managing Dementia Across the Continuum
Care Coordination Practice Tool
Community Based Service Provider Practice Tool
After A Diagnosis
While the recommended practices in these tools are not state-specific, many of the
resources referenced are specific to Minnesota. The resource sections of these tools can
be adapted to reflect resources specific to your geographic area.
To access ACT tools visit: http://actonalz.org/provider-practice-tools
Alzheimer’s disease (AD) is a progressive neurodegenerative disease – symptoms
become more severe over time until eventually the brain can no longer control autonomic
functions like swallowing, and death results. AD is thought to begin as a disorder of
synaptic function; as disease progresses, synapses are lost and finally neurons die.
During the early phases of the disease, before there is a widespread loss of neurons,
symptoms are subtle or might even be absent. Understanding the pathobiological
mechanisms that lead to neuron death is essential for the development of therapies to halt
or delay the disease process. Currently, the field of AD research resembles a large,
unfinished jigsaw puzzle with many missing pieces – the big picture is known (the
clinical manifestations of disease) and some pieces are in place, but many pieces have yet
to be found and/or fit together. This module will review what we have learned about the
biology of AD from studies of model systems (e.g., cultured brain cells and mice
genetically modified to mimic particular aspects of AD). Studies with human subjects
will be discussed in another module.
In addition to pronounced synapse and neuron loss, AD is characterized by the
presence of two neuropathological lesions: extracellular amyloid plaques and intracellular
neurofibrillary tangles (NFTs). Amyloid plaques are formed from aggregated amyloid
beta (Aβ) protein, while NFTs are comprised of abnormally processed tau, a protein
normally associated with the microtubules that form the cytoskeleton. The identification
of Aβ and tau as major components of the lesions seen in AD patients led researchers to
focus their attention on these proteins, and this module will concentrate on the roles that
Aβ and tau might play in the disease process. However, these are certainly not the only
active areas of research within the AD field. There are several excellent on-line
resources for keeping up with hot topics in AD research, including the Alzheimer
Research Forum and the National Institute on Aging’s Alzheimer’s Disease Education
and Referral Center.
Proposed Causes of Alzheimer’s Disease
Before discussing mechanistic studies, we will briefly review the history of the
etiology of AD. The causes of AD are not known. In less than one percent of all cases,
AD is strongly associated with a genetic mutation; individuals possessing this mutation
are certain to get the disease (discussed below). However, most cases of AD arise
sporadically, with age being the greatest risk factor for the disease. Whatever the
underlying causes(s) may be, many scientists believe that both the genetically-determined
and the sporadic forms of AD share common biochemical and pathogenic mechanisms.
The Aluminum Hypothesis
One of the earlier hypotheses to be put forward linked aluminum and Alzheimer’s
disease. In the 1960s, researchers found that injecting rabbit brains with aluminum salts
caused progressive neurodegeneration that was accompanied by neurofibrillary pathology
similar to the NFTs seen in AD (1, 2). This discovery was reinforced by later findings of
elevated aluminum levels in the brains of AD patients (3) and a correlation between
incidence of AD and levels of aluminum in drinking water (4). In recent years, support
for the aluminum hypothesis has waned as methodological flaws in the original studies
have surfaced and subsequent, larger studies have failed to establish any link between
aluminum and AD (5, 6).
The Pathogen Hypothesis
The pathogen hypothesis posits that AD may be caused by microbial infections.
Pathogens including herpes simplex virus-1 (HSV-1), Chlamydophyla pneumoniae, and
several types of spirochetes1 have been implicated in the development of AD pathology
(7, 8). While dormant HSV-1 is found in nearly 90% of adults aged 50-80 years,
involvement of the brain in infection is rare (9). However, herpes simplex encephalitis
has been shown to affect the frontal and temporal cortices – areas consistently involved in
AD pathology (10). C. pneumoniae and spirochetes, in contrast, have simply been found
in greater proportions in the brains of AD subjects (11). Again, many studies have failed
to replicate these findings and a causal link between AD and these pathogens cannot be
inferred.
The Cholinergic Hypothesis
One of the oldest hypotheses as to the cause of AD is the cholinergic hypothesis.
In AD, there is a loss of basal forebrain-based cholinergic neurons2 (12, 13). Proponents
of the cholinergic hypothesis point to studies indicating that administration of
anticholinergic drugs can produce cognitive deficits similar to those seen in AD (14, 15).
Cholinesterase inhibitors – drugs that inhibit the breakdown of acetylcholine – are one of
only two classes of drugs currently approved by the FDA for the treatment of AD
symptoms. Donepezil (Aricept), galantamine (Razadyne), and tacrine (Cognex) belong
to this class of drugs. Challenges to the cholinergic hypothesis predominantly come from
recent studies that have failed to find a decrease in choline acetyltransferase3 (ChAT)
activity in the brains of subjects with mild cognitive impairment (MCI) or mild AD (1618). In fact, one of these studies actually found elevated ChAT activity in the
hippocampi and frontal cortices of MCI subjects (17). Collectively, the evidence tends to
suggest that cholinergic deficits and pathology are not the primary causes of AD, but are
rather features of late-stage AD that might contribute to the cognitive symptoms observed
at this stage.
The Oxidative Stress Hypothesis
1
Spirochetes are double-membrane bacteria with long, helical cells. Spirochetes are chemotrophic,
meaning that they obtain energy via oxidation of electron donors in their environments.
2
These neurons project to many regions of the cortex
3
Choline acetyltransferase (ChAT) is the enzyme responsible for the synthesis of the neurotransmitter
acetylcholine. ChAT levels or activity are often used to monitor the functional state of cholinergic
neurons.
The oxidative stress hypothesis focuses on the late onset and slow progression of
AD, in that the accumulation of oxidative damage over time is a central feature of AD
pathogenesis. Oxidative stress is associated with the presence of reactive oxygen species
and is caused by the biological system’s inability to detoxify the reactive species or repair
resulting damage (19). Due to its high oxygen consumption, high concentration of
polyunsaturated fatty acids, and relatively low antioxidant enzymes, the brain is relatively
susceptible to oxidative damage (20). Support for the oxidative stress hypothesis has
come from observations that – compared to control brains – AD brains show increased
oxidative damage to nucleic acids, proteins, and lipid membranes (21, 22). Multiple
studies have found elevated markers of oxidation in the brains and cerebrospinal fluid
(CSF) of AD patients (23). Furthermore, studies of oxidative stress in animal models of
AD have found evidence of oxidative damage (24). Unfortunately, clinical trials of
antioxidants have failed to mitigate AD progression (25, 26).
The Type III Diabetes Hypothesis
Yet another hypothesis points to a link between diabetes and Alzheimer’s disease,
with some even calling for AD to be renamed “Type III diabetes.” This hypothesis is
based on the observation that when AD brains are imaged with fluorodeoxyglucose
positron emission tomography (FDG-PET), there is reduced glucose utilization in
characteristic brain regions (27). This finding led some scientists to suggest that
defective insulin signaling was the cause of these FDG-PET abnormalities (28).
However, it must be stressed that factors such as decreased energy demands by
malfunctioning neurons, impaired blood flow to the diseased brain, and/or deranged
coupling between neuronal demand and blood vessel response might also underlie the
observed decreases in glucose uptake.
Nonetheless, both decreased insulin production and increased insulin resistance
have been associated with AD (29). It is the combination of these aspects (elements of
both Type I and Type II diabetes) that has led to the somewhat controversial “Type III
diabetes” label. Analysis of postmortem AD brains has revealed that components of the
insulin- and insulin-like growth factor- signaling pathways are decreased (30), and that
these decreases become more pronounced with increasing disease severity (31).
Evidence from animal models has provided further support for the Type III diabetes
hypothesis. Rats exposed to streptozotocin (STZ) – a compound that causes diabetes
when metabolized in insulin-producing cells – exhibit cognitive deficits and significant
neurodegeneration similar to what is seen in AD (32). Additionally, it has been observed
that when individuals with AD are given insulin, they show improved performance on
cognitive tasks craft (33, 34); however, it should be noted that insulin also improves
performance in “normal” subjects, suggesting that insulin acts as a general cognitive
enhancer (35).
The Amyloid Cascade Hypothesis
The Amyloid Cascade Hypothesis posits that aberrant aggregation of Aβ triggers
a multi-step cascade in which synaptic dysfunction, pathologic processing of tau, and
neuroinflammation eventually lead to neuron death and dementia (36, 37). The strongest
evidence in favor of the Amyloid Cascade Hypothesis comes from genetic studies. As
mentioned above, there are rare genetic mutations that destine a person to develop AD;
all of these AD-causing mutations increase the production of total Aβ or its propensity to
aggregate (reviewed in (38)). Amyloid beta is formed from the sequential cleavage of
amyloid precursor protein (APP) by the enzymes beta (β)- and gamma (γ)-secretase. ADlinked mutations have been found in the gene encoding APP and in the genes encoding
presenilins (PS) 1 and 2, sub-units of γ–secretase (an up-to-date compendium of these
mutations is maintained by the Alzheimer Research Forum). Conversely, a newlydescribed mutation in APP that results in decreased production of Aβ protects against
sporadic AD (39). Taken together, these studies are consistent with the part of the
Amyloid Cascade Hypothesis that postulates that aggregated Aβ initiates the disease
process.
There is also experimental support for the hypothesis that tau acts downstream of
Aβ. When injected into the brains of mice expressing transgenic human tau, Aβ
exacerbates tau pathology (40, 41). Genetic depletion of tau has been shown to prevent
Aβ-induced toxicity in vitro (42) and cognitive deficits in mice that express transgenic
human APP (43).
Critics of the Amyloid Cascade Hypothesis raise two major objections. First,
transgenic mice overexpressing human APP with AD-linked mutations exhibit increased
Aβ aggregation but do not develop neurofibrillary tangles or neuronal loss, features of
human AD (44). Proponents of the Amyloid Cascade Hypothesis point to the many
differences between mouse and humans as possible explanations; these differences
include forms of tau, neuroinflammatory responses, susceptibility to synaptic-activityrelated neuron damage, and lifespan. The second critique of the Amyloid Cascade
Hypothesis concerns the fact that drugs targeting Aβ have failed to mitigate AD
progression in clinical trials (reviewed in (45)). However, the likely reason for the
failures of these drugs is that they were administered too late. The Amyloid Cascade
Hypothesis predicts that anti-amyloid therapies should be effective when administered
very early in the disease course, before processes downstream of Aβ become selfsustaining.
Despite the criticisms raised against it, the Amyloid Cascade Hypothesis is
supported by a preponderance of the evidence and is the predominant model driving most
AD research today.
Why Does Aβ Accumulate?
If, as the Amyloid Cascade Hypothesis proposes, the accumulation of Aβ
aggregates is indeed the event that triggers AD, the question naturally arises as to what
causes this accumulation. The rate of accumulation of Aβ in the brain is a result of the
relative rates of production and clearance of Aβ. In the rare familial forms of AD
(discussed above), genetic mutations lead to the overproduction of Aβ aggregates. In
sporadic AD, accumulation is most likely due to a decline in the ability to eliminate Aβ
from the brain (46). Amyloid beta can be removed from the brain slowly via fluid flow
from the interstitial space4 into the bloodstream, but this process is inefficient and is
responsible for only 10-15% of total Aβ clearance (47). Instead, there exist two major
pathways of Aβ clearance: degradation by enzymes within the brain and receptormediated transport from the brain into the blood.
Two enzymes are able to degrade Aβ: insulin degrading enzyme (IDE) (48) and
neprilysin (NEP) (49). In transgenic mice with reduced levels of IDE, there is an
increased level of Aβ in the brain (50); conversely, transgenic overexpression of IDE
results in substantial reductions in soluble Aβ, amyloid plaques and premature death in
mice expressing transgenic APP (51). Overexpression of neprilysin in cultured neurons
(52) and in mice (49) has been found to increase the rate of degradation of Aβ and
decrease the number of amyloid plaques in APP transgenic mouse brains (53).
Receptor-mediated transport is also responsible for a large portion of Aβ
clearance. The lipoprotein receptor-related protein (LRP) binds to Aβ and facilitates its
binding to brain capillaries. Once bound to the capillaries, Aβ is transferred across the
blood-brain barrier into the bloodstream (54). Relatively low LRP activity has been
found in AD patients (55), and mutation or dysfunction of LRP has been shown to
correlate with increased Aβ deposition in APP transgenic mouse brains (56).
In sporadic AD, there are also genetic factors that influence an individual’s risk of
developing the disease; these genetic factors are distinct from the rare mutations
(discussed above) that predestine a person to develop the disease. People with specific
alleles of certain genes have a greater or lesser chance than average of developing AD.
The gene with the strongest effect on the risk of sporadic AD encodes apolipoprotein E
(ApoE). Compared to the general population, individuals with two copies of the “ε4”
allele of this gene are 10-15 times more likely to develop AD (57). While nobody knows
the exact role that ApoE plays in AD, animal studies have shown that the rate of Aβ
clearance from the brain is differentially regulated by the various isoforms of ApoE (58).
Aβ: Plaques vs. Oligomers
In the early years of Alzheimer’s disease research, scientists focused their
attention on the neuropathology visible under the light microscope: amyloid plaques and
neurofibrillary tangles. However, studies in both humans and animal models of AD
4
The space surrounding the cells in the brain
generally have shown that plaques do not correlate with cognitive dysfunction (59-62).
These observations, coupled with the evidence supporting the Amyloid Cascade
Hypothesis (see above), suggest that other forms of Aβ, rather than plaques, are
responsible for memory decline in AD.
Amyloid plaques are composed of fibrillar Aβ and are insoluble in the detergentcontaining solutions commonly used to extract proteins from tissues. By contrast,
“oligomers” are detergent-soluble Aβ assemblies. Amyloid beta oligomers can be
formed in vitro from synthetic Aβ, and, more importantly, have been found in human
brains and in the brains of mice genetically engineered to express human amyloid
precursor protein (63). Over the last decade, evidence has accumulated that strongly
suggests that Aβ oligomers are responsible for cognitive impairment. While many of
these studies employed synthetic Aβ oligomers, and are therefore of uncertain relevance,
a few laboratories have attempted to identify and study the effects of oligomers that are
naturally generated in the brains of AD patients or transgenic mouse models. Some of
these studies are reviewed below.
Aβ*56
In Tg2576 mice (mice carrying a human APP transgene with an AD-linked
mutation), cognitive decline begins at around 6 months of age – months before plaques
appear in the brain (62). This observation led researchers to look for an Aβ species
whose appearance coincided with the onset of cognitive decline. In 2006, scientists at the
University of Minnesota described “Aβ*56,” a 56-kDa Aβ assembly5 that might be
responsible for memory dysfunction (64). In Tg2576, Aβ*56 first appears at 6 months of
age, and its levels correlate with cognitive dysfunction in the Morris water maze – a test
of spatial memory function. To test whether Aβ*56 is sufficient to induce memory
problems, researchers isolated Aβ*56 from the brains of transgenic mice and injected it
into the brains of young, healthy rats; these rats rapidly displayed memory problems, as
evidenced by poor performance in both the Morris water maze and a lever-pressing task
(64).
Tg2576 mice, like other APP transgenic mice, do not fully recapitulate AD – they
have subtle cognitive deficits but no NFTs or widespread neuron loss – and are thought to
model the earliest stages of the disease. For this reason, it was suggested that Aβ*56 has
a role very early in AD, and that it might even be the Aβ species that triggers the
Amyloid Cascade (64). Support for this idea came from two studies published in 2013.
To understand the results of these studies, one must recall that AD has a long
presymptomatic phase, possibly lasting two decades or more. During this time, people
appear to be cognitively healthy, but sensitive memory tests, brain imaging studies, or
analysis of cerebrospinal fluid can reveal evidence of an unhealthy brain (65-69). If
5
Aβ*56 is most likely an aggregate of 12 Aβ molecules.
Aβ*56 really does have a role during the earliest phase of AD, it should be found in the
brains of people who appear cognitively normal but who show signs of a compromised
brain. This is indeed what was found. In the brains of subjects who were cognitively
normal at the time of death, levels of Aβ*56 correlated negatively with levels proteins
found in synapses (i.e., higher levels of Aβ*56 were associated with lower levels of
synaptic proteins) and positively with pathological forms of tau that precede the
appearance of NFTs (70). In cerebrospinal fluid collected from cognitively normal older
adults, Aβ*56 was elevated in individuals at risk for developing AD and correlated
strongly with levels of tau (elevated tau in the CSF is believed to be a marker of neuronal
injury)(71).
Dimers
After the discovery of Aβ*56, researchers sought to identify other synaptotoxic
Aβ oligomers that might be present in the brains of individuals with AD. In 2008, it was
first shown that extracts of AD brain can modulate two forms of synaptic plasticity
believed to be the cellular bases for learning and memory: long-term potentiation (LTP)6
and long-term depression (LTD)7. When applied to slices of rodent brain, AD brain
extracts inhibited LTP and enhanced LTD. After looking into which component of the
brain extract was responsible for these effects, researchers concluded that Aβ dimers
(pairs of Aβ proteins assembled together) were acting as the toxic species (72). Further
studies showed that injecting rodent brains with dimer-containing cerebrospinal fluid (73)
or dimer-containing brain extracts (72) resulted in impaired memory function or synaptic
plasticity. However, recent research has shown that Aβ dimers quickly form stable
protofibrils8, which can mediate synaptotoxicity. That being said, it has been suggested
that dimers are not neurotoxic in themselves; but that said toxicity requires their further
assemblage into protofibrils (74). It should be noted that dimers are elevated in people
with Alzheimer’s dementia (70, 75) .
Amylospheroids
Although they have not been as thoroughly studied as other oligomers,
amylospheroids are suggested to play a role in AD. Amylospheroids are spherical
aggregates of Aβ protein and, importantly, are found in the brains of people with AD but
not in cognitively healthy, elderly individuals. Additionally, amylospheroids isolated
from AD brains kill cultured neurons (76) with the most toxic form of amylospheroid
appearing to be an aggregate of ~32 Aβ molecules (77). Although these initial findings
6
Long-term Potentiation (LTP) is a long-lasting increase in the strength of transmission at particular
synapses.
7
Long-term Depression (LTD) is a long-lasting decrease in the strength of transmission at particular
synapses.
8
Protofibrils are considered a fibrillar intermediate which acts as a precursor to plaques.
are intriguing, an effect of brain-derived amylospheroids on synaptic plasticity or
cognition has yet to be demonstrated.
Are Plaques Neuroprotective?
A majority of current research implies that plaques are not responsible for
cognitive impairment, but does this mean that plaques might actually protect brain
function by sequestering toxic Aβ species? Given the finding that amyloid plaques are
relatively inert9 unless they are solubilized to release Aβ dimers, it has been proposed that
plaques actually help to detoxify harmful, synaptotoxic molecules by quarantining them
into insoluble, harmless assemblies (72). Based on autopsy and neuroimaging studies, it
has been estimated that ~40% of cognitively healthy individuals have substantial
numbers of amyloid plaques in their brains (38). Many scientists have interpreted this
observation as evidence that plaques form very early in the disease course, long before
cognitive symptoms are apparent. However, Charles Glabe and colleagues have offered
the intriguing suggestion that preferential aggregation along a fibrillar pathway might
explain why these individuals remain cognitively intact: they do not produce
synaptotoxic oligomers (78). This theory is supported by recent research identifying
small molecules that reduce Aβ toxicity by accelerating fibril formation (79, 80).
Challenges of Studying Aβ Oligomers
While there is a great deal of data supporting the existence of toxic Aβ oligomers,
there is some debate as to whether these specific oligomers are present in vivo (81). It is
difficult to determine which oligomers are actually present in living brains and to
demonstrate their effects in situ (i.e., located within the brain where they are produced, in
contrast to their effects when dispersed and applied to cultured cells or host brains).
Currently, there are no known reagents that bind to specific Aβ oligomers and can thus be
used to demonstrate the presence of a particular oligomer in situ. Biochemical studies,
combining some method of separating proteins by size with immunological detection of
Aβ, have provided evidence for the presence of specific assemblies in brain homogenates
or cerebrospinal fluid. These biochemical studies, while theoretically straightforward,
are actually quite challenging. When present in the brain, Aβ oligomers are generally
found at low levels; isolation and/or characterization usually require detergent-containing
buffers, which can both artificially create and break apart oligomers. Additionally, some
oligomeric species may be too unstable to reliably detect and measure in brain
homogenates. As a result of these experimental challenges, leaders in the field recently
came together to discuss more stringent criteria for supporting claims that a specific
oligomer has disease relevance.
9
(i.e., not inhibiting long-term potentiation)
Potential Targets of AB
Amyloid beta may mediate its neurotoxic effects by binding to a variety of
targets. Many groups have attempted to identify these molecular targets of Aβ and to
determine which interactions induce pathological changes in neurons. On the one hand,
it has been reported that Aβ oligomers insert themselves into cell membranes, creating
pores that allow ions to flow into and out of cells. An abnormal influx of calcium ions
may then activate calcium-sensitive enzymes which promote synaptic dysfunction and/or
cell death (82). On the other hand, there is a plethora of reports showing interactions
between Aβ species and specific membrane receptors or intracellular proteins. A few of
these targets are described below; this selection is meant to convey the diversity of Aβ
targets and is by no means complete. Other posited targets can be found in reviews by
Ashe and Zahs (38) and Larson and Lesné (63).
Cellular Prion Protein (PrPc)
Cellular prion protein (PrPc) was identified as a potential target of Aβ in an
unbiased screen searching for proteins that bind to Aβ oligomers (83). This observation
generated a great deal of excitement, as PrPc is the parent form of the aberrantly folded
proteins that cause spongiform encephalopathies (e.g., Creutzfeldt–Jakob disease in
humans, mad cow disease in cattle, and scrapie in sheep); many researchers quickly
embraced the idea that AD was part of a larger family of neurodegenerative diseases. It
was reported that antibodies that block the binding of Aβ to PrPc prevented deleterious
effects of Aβ on synaptic plasticity in vitro (83, 84) and that APP transgenic mice lacking
PrPc had normal memory function (85). However, other laboratories have challenged
these findings, reporting that Aβ-induced deficits in memory function (86) and LTP (87,
88) cannot be rescued by ablation of PrPc. These discrepant results are probably due to
differences in the precise species of Aβ that were responsible for inducing neuronal
dysfunction in each study. These studies employed a variety of synthetic oligomers and
different lines of transgenic mice, each of which generates its own, age-dependent
complement of specific oligomers. Among brain-derived oligomers, only dimers have
been shown to interact with PrPc (89). While dimer-mediated deficits might be mediated
by PrPc, it is likely that Aβ*56-mediated deficits are PrPc-independent.
Binding of Aβ to PrPc activates Fyn kinase10 (89). This kinase regulates the
trafficking of the N-methyl-D-aspartate type of glutamate receptor (NMDAR) at the
synapse (90). NMDARs play a critical role in learning and memory, and excessive
activation of these receptors is thought to lead to neuron death (91). Although this has
10
Fyn kinase is a protein that phosphorylates a specific amino acid of target proteins. Generally, the
proteins phosphorylated by Fyn kinase are involved in signaling pathways.
yet to be demonstrated directly, it is tempting to speculate that alterations in NMDAR
function occur downstream of Aβ binding to PrPc.
Glutamate transport
As mentioned above, NMDARs are believed to play a role in neuron survival as
well as in synaptic plasticity. “Synaptic NMDARs” are present in dendritic spines,
directly apposed to pre-synaptic terminals; activation of these receptors stimulates
intracellular pathways that promote neuron survival (92). NMDARs can also be located
farther away from the pre-synaptic terminals; activation of these “extrasynaptic”
NMDARs suppresses the pro-survival pathways and promotes cell death (93). Normally,
glutamate is confined to the immediate area of the synapse; some glutamate is recycled
back into the presynaptic terminal by transporters located on the terminal, but most is
taken up by transporters located on astrocytes (glial cells) whose processes surround the
synapse. However, under some conditions, glutamate uptake cannot keep up with
glutamate release, and glutamate “spills over” from the synapse. When this happens,
extrasynaptic NMDARs are activated. Amyloid beta oligomers have been shown to
increase activation of extrasynaptic NMDARs (94), likely by inhibiting glutamate uptake
(95).
Alpha7-nicotinic Acetylcholine Receptors
A significant decrease in the number of cholinergic neurons is characteristic of
AD brains (see above). Very low (10-8 M) concentrations of Aβ have been shown to
reduce cholinergic synaptic transmission (96). In particular, the alpha7-nicotinic
acetylcholine receptor (a7nAchR), a pre-synaptic receptor, has been shown to have a high
affinity for Aβ (97). Aβ 1-42, acting via a7nAchRs, disrupts the release of multiple
neurotransmitters (98).
Aβ-ABAD
In AD, widespread mitochondrial dysfunction leads to decreased cellular
metabolism (reviewed in (99)). Amyloid beta peptide-binding alcohol dehydrogenase
(ABAD) is localized in the mitochondria and is a candidate for the receptor through
which Aβ exerts its effects on the mitochondria. APP transgenic mice that also
overexpress ABAD have increased cell death and an increase in reactive oxygenated
species (ROS); experiments have indicated that these ROS originate from the
mitochondria (100). The interaction between Aβ and ABAD is a possible mechanism
through which Aβ exerts toxic effects on neuronal metabolism.
Its multiple forms and tendency to stick to itself and to other proteins makes the
identification of Aβ’s actual targets quite challenging. One approach to this problem is to
genetically manipulate levels of potential targets in Aβ-generating transgenic mice and
observe how these manipulations affect disease-related phenotypes. However, this
approach has its drawbacks: compensatory changes in other proteins or developmental
abnormalities might obscure the effects of the Aβ-target interaction. Despite the
challenges of identifying the actual targets of Aβ, this work is essential for the
development of new and effective therapies for AD.
Tau
Genetic evidence, cited above, provides strong support for the hypothesis that the
accumulation of Aβ triggers AD. What, then, is the role of tau? Abnormally processed
tau is the major component of neurofibrillary tangles, one of the pathological hallmarks
of AD. However, until the end of the 20th century there was some debate as to whether
abnormal tau contributed to the pathogenesis of AD or whether it was merely a byproduct of the disease (101). In 1998, it was reported that thirteen separate families with
an inherited form of frontotemporal dementia (FTD)11 all had mutations in the gene
coding for tau (102). These genetic studies thus provided evidence that abnormal forms
of tau can cause neurodegeneration. Subsequently, it was shown that transgenic mice
expressing human tau with an FTD-linked mutation exhibit pronounced
neurodegeneration (103, 104). Notably, many of the post-translational modifications in
tau that are promoted by FTD-linked mutations are also seen in AD brains (103, 105).
These observations are consistent with the hypothesis that AD-related forms of Aβ
promote pathological processing of tau, but that it is misprocessed tau that mediates
neuron loss. Exactly which form of tau is toxic is one of the outstanding questions in AD
research today.
Hyperphosphorylated Tau in AD
Despite being most widely known for its role in Alzheimer’s, the tau protein is
actually found in all brains – even those brains that are perfectly healthy. In a normal
brain, tau’s primary role is in assembling tubulin12 into microtubules13 and then
stabilizing and maintaining these microtubules in the cytoskeleton of axons. Tau is a
phosphoprotein, which means that there are sites on the protein that can bind to – and be
modified by – phosphate (PO4) groups. Although there are dozens of these sites on the
tau protein, normal, non-pathogenic tau generally contains 2-3 moles of phosphate per
mole of tau (106). During the 1980’s, researchers analyzing autopsied AD brains
11
“Frontotemporal dementia and parkinsonism linked to chromosome 17,” formerly known as Picks’
disease, is a progressive neurodegenerative disorder characterized by disturbances of behavior, cognition
and movement
12
The constituent protein of microtubules of cells, which provide a skeleton for maintaining cell shape
and is thought to be involved in cell motility (http://medical-dictionary.thefreedictionary.com).
13
Composed chiefly of tubulin, microtubules are involved in maintaining cell shape and moving organelles
around within the cell. Microtubules are also involved in cell division.
discovered that the paired helical fragments (PHFs) which form into neurofibrillary
tangles (NFTs) are made up of abnormally phosphorylated tau (107, 108). Additional
research revealed that this abnormal tau contains 5-9 moles of phosphate per mole of
protein – a phosphorylation level that is 3-4 times higher than what is seen in normal,
healthy tau (109-111). Interestingly, the manner in which tau is phosphorylated (e.g., the
amount of phosphorylation, where on the tau protein the phosphorylation occurs, etc.)
regulates how tau interacts with microtubules. When tau becomes hyperphosphorylated
(too many sites on the tau protein are phosphorylated), it loses its ability to bind to
microtubules (112, 113).
Possible Causes of Hyperphosphorylation
Although the specific mechanisms underlying tau hyperphosphorylation in AD
are unknown, there are many theories as to what factors drive the change from healthy
tau to pTau. Some of the more well-studied theories are outlined below.
The Effect of Aβ on Tau
A number of studies have shown that Aβ can facilitate tau hyperphosphorylation
and NFT formation. When Aβ is added to rat hippocampal and human neuronal
cultures14, it induces tau phosphorylation and loss of microtubule binding (114). It has
also been demonstrated that injecting Aβ into the brains of transgenic mice15 markedly
increases the number of NFTs in the amygdala (40). Additionally, experiments have
shown that crossing a transgenic line overexpressing mutant APP with another,
independent line overexpressing mutant tau leads to enhanced tau pathology (41).
Conversely, administration of antibodies directed against Aβ reversed tau pathology in a
transgenic mouse line that expresses human genes for both mutant APP and tau (115).
Taken together, these findings suggest that Aβ promotes the formation of pathological
forms of tau.
GSK-3
Glycogen synthase kinase 3-beta (GSK-3β) is a microtubule-associated protein
(MAP) that facilitates the phosphorylation of proteins at serine and threonine residues. It
has long been known that GSK-3β can phosphorylate tau (116-118), and it turns out that
Aβ is able to activate GSK-3β by interfering with the pathway that normally leads to
GSK-3β inhibition (119). Therefore, it is possible that GSK-3β activation is one of the
paths through which Aβ facilitates tau hyperphosphorylation.
14
Neuronal culturing is a process in which cells are grown under controlled conditions, outside of their
natural environment (http://en.wikipedia.org/wiki/Cell_culture).
15
The transgenic mouse line used for this study overexpresses a form of tau that is linked to
frontotemporal dementia
Caspase Activity
The caspases are a family of twelve proteolytic16 enzymes that are involved in
inflammation and cell death. Activated caspases-8 and -9 have been found in AD brains,
where their presence appears to precede tau hyperphosphorylation and NFT formation
(120). In vitro studies have shown that caspases-3, -7, and -8 (and, to a lesser degree,
caspases-1 and -6) are able to cleave tau into a truncated form which more rapidly
assembles into filaments (121, 122). While the exact mechanisms by which the caspases
affect tau are unknown, caspase-driven cleavage of tau appears to modify the protein in
such a way as to facilitate the formation of NFTs.
Other Possible Suspects
In addition to looking at Aβ, GSK-3β, and the caspase family, researchers have
studied many other factors that could potentially promote tau hyperphosphorylation.
These factors include (but are not limited to):




The interaction of diet, genetics, and cell oxidation (123, 124)
Certain insulin deficiencies (125, 126)
Vitamin deficiencies (124) (127)
Cholesterol level (123, 128)
The exact mechanism by which normal tau is modified into pTau remains unknown; but
regardless of what causes tau to become hyperphosphorylated, it is well known that pTau
aggregates into NFTs. Unfortunately, the exact role that NFTs play in AD is not entirely
clear.
The Role of NFTs
Prior to ~2005, NFTs were believed to be highly involved in mediating
neurodegeneration and dementia in AD. In fact, a number of studies showed that the
presence of NFTs is associated with cognitive decline and synaptic malfunction (40, 41,
129, 130). However, recent studies have shown that while NFTs are one of the primary
markers of AD, they do not appear to be the cytotoxic17 form of tau.
In 2001, it was shown that overexpression of tau in Drosophila (fruit flies) led to
neurodegeneration without the formation of NFTs (131). This finding was reinforced in
2005 with the discovery that NFT formation is separate from neuron loss and cognitive
dysfunction in transgenic mice. When transgenic tau was suppressed in mice expressing
a regulatable tau transgene18, NFTs continued to accumulate but neuron loss was arrested
16
Proteolytic enzymes act on proteins by cleaving them into smaller fragments.
Cell-death causing
18
A transgene that allows tau production to be turned on or off
17
and memory function recovered (104). In the same line of transgenic mice, it was seen
that neuron loss preceded neurofibrillary pathology in some regions of the brain and that
this pathology occurred without neuron loss in other areas (132). Additional support for
the “NFTs ≠ cell death” theory came in 2006 with results showing that in a mouse model
with mutant human tau, inhibition of tau hyperphosphorylation led to delayed
development of motor dysfunction – without affecting NFT numbers (133).
The Search for the Toxic Form of Tau
Several candidates have been proposed as the toxic form of tau. None of these
have been proven to be the primary factor underlying tau-induced pathology, but initial
results indicate that they may be involved in the disease process.
Tau Oligomers
Like Aβ, tau has the ability to form oligomers. Although research into this topic
is ongoing, it is possible that tau oligomers, not tangles, are the primary pathological
aggregates in AD. Preparations of tau oligomers are more toxic to cultured
neuroblastoma cells than are preparations of tau filaments – the form of tau that makes up
NFTs (134). A 170-kDa tau multimer, possibly a dimer of hyperphosphorylated tau, was
found to correlate significantly with cognitive dysfunction in transgenic mice expressing
human tau with a mutation linked to frontotemporal dementia (i.e., higher levels of the
tau multimer are associated with reduced cognitive function) (135). These results have
yet to be replicated, but the idea that tau multimers may be important in the disease
process is gaining traction in the field.
Toxic Tau Fragments
It is known that tau can be cleaved by certain enzymes (e.g., proteases such as
caspases-3, -7, and -8), and it is possible that the smaller tau fragments that arise from
this cleavage may contribute to neurotoxicity.
When tau is cut by caspase-3, a truncated 50-kDa cleavage product is formed. In
vitro studies have correlated high levels of this cleavage product with an increased
incidence of cell death (136) and faster, more extensive tau filament assembly (122). In
addition to caspase, tau can also be cleaved by calpain, another protease (137). It is well
known that calpain can cut tau into a 17-kDa fragment; recent in vitro research has
indicated that this calpain-cleavage precedes tau phosphorylation (138). This indicates
that the tau cleavage product created by calpain may facilitate tau phosphorylation.
While it is unknown whether tau fragments are actually toxic in vivo, these cleavage
products may turn out to play a key role in the disease process.
Tau Mislocalization
When the tau protein becomes hyperphosphorylated, it loses its ability to bind to
(and maintain) microtubules. In addition to aggregation and NFT formation, an
overexpression of hyperphosphorylated tau has been found to result in tau mislocalization
– a process in which tau, which is normally found only in the axon and soma, diffuses
into the dendritic spines (139). This mislocalized tau is distinct from PHFs/NFTs. In
cultured neurons, tau mislocalization to spines is accompanied by deficits in synaptic
transmission (139). If it turns out that tau mislocalization causes synaptic and cognitive
deficits in vivo, preventing tau from mislocalizing may help to rescue some of the
cognitive symptoms seen in AD.
Spread of AD Pathology Throughout the Brain
Neuropathological studies have shown that plaques and NFTs spread
systematically through the brain (140). NFTs first appear in the entorhinal cortex19
before spreading to the limbic20 and association21 cortices, while amyloid plaques are first
seen in association cortices and subsequently appear in primary cortical areas and the
hippocampus. These observations led to the question of whether tau and amyloid
pathology can spread between neurons.
Evidence that tau can spread between neurons has been provided by both in vitro
and in vivo studies. Tau aggregates can be transferred between cultured mammalian cells
(141), and injection of brain extracts from NFT-bearing mice into wild-type, nontransgenic mice induces the appearance of tau fibrils in previously healthy neurons, a
phenomenon known as “tau seeding” (142). Using transgenic mice in which human tau
is expressed only in the entorhinal cortex, two independent groups demonstrated the
spread of neurofibrillary pathology first from the entorhinal cortex to the dentate gyrus,
then from the dentate gyrus to other subfields of the hippocampus (143, 144). These
observations are consistent with the trans-synaptic spread of tau “seeds.”
The proliferation of amyloid pathology has also been studied. Several
laboratories have shown that injection of Aβ into the mouse brain initiates plaque
deposition at the injection site and that this deposition then spreads between axonallyinterconnected regions (145-147). Additionally, when transgenic human APP is
expressed in the entorhinal cortex, amyloid plaques spread from the entorhinal cortex to
the dentate gyrus (148).
19
The entorhinal cortex is located in the medial temporal lobe, and is involved in memory and spatial
navigation.
20
The limbic cortex is involved in a range of factors including emotion, behavior, long-term memory, and
motivation.
21
The association cortex contain the expanses of the cerebral cortex that are associated with advanced
stages of sensory information processing, multisensory integration, and sensorimotor integration
(http://medical-dictionary.thefreedictionary.com/association+cortex).
Taken together, the results of these in vivo and in vitro studies suggest that
amyloid and tau pathology may undergo neuron-to-neuron transmission. However,
pathophysiological consequences of the spread of these entities have yet to be
convincingly demonstrated. It is important to mention that media reports of these studies
have been misinterpreted to mean that AD is a contagious disease – this is not the
implication of these studies.
Polyproteinopathy of Alzheimer's Disease
Recently, researchers have started to move beyond the notion that pathogenic Aβ
and tau are the sole culprits in Alzheimer's disease and have examined the possible
involvement of additional proteins normally associated with other neurodegenerative
diseases (149).
Alpha-synuclein is a major component of Lewy bodies, the pathognomonic
lesions of Parkinson’s disease. In addition to plaques and NFTs, Lewy bodies have been
observed in a substantial number of individuals who meet the neuropathological criteria
for AD (150-152), and synuclein co-pathology increases the risk of clinical dementia in
those with AD pathology (plaques and NFTs) (153-155). In a recent study, levels of
soluble alpha(α)-synuclein were reported to be two-fold higher in AD brains than in
control brains, and cognitive function prior to death more strongly correlated with levels
of soluble α-synuclein than with levels of soluble tau or A in these brains (156). In
vitro, Aβ promotes the formation of abnormal α-synuclein species (157), and Aβ and αsynuclein can induce recombinant human tau to form cytotoxic aggregates (158).
Introduction of a transgene encoding α-synuclein (with a Parkinson disease-linked
mutation) exacerbates cognitive dysfunction and amyloid plaque and NFT pathology in
mice that also express transgenes for human APP (with an AD-linked mutation) and tau
(with a mutation linked to frontotemporal dementia) (159). These studies of the
interactions between A, tau, and α-synuclein in vitro and in vivo are consistent with the
hypothesis that AD is a “polyproteinopathy” in which A, tau, and α-synuclein act
synergistically or additively to impair cognition and cause neurodegeneration.
Alpha-synuclein, Aβ, and tau are not the only proteins that might play a role in
AD. TAR DNA-binding protein 43 (TDP-43) inclusions, which form the characteristic
neuropathological lesions of amyotrophic lateral sclerosis and the FTLD-U variant of
frontotemporal degeneration, have been reported in 25% to 50% of AD cases (160-163).
It is not known whether the co-existence of additional lesions with amyloid plaques and
NFTs represents a pathological state that promotes protein misaggregation, the
coincidental co-occurrence of independent pathological processes, or an essential
contribution of α-synuclein and/or TDP-43 to the pathogenesis of AD.
Conclusion/Future Directions
Elucidating the mechanisms of Alzheimer’s disease is a daunting task.
Alzheimer’s is a chronic disease; it is now believed that, including its presymptomatic
phase, AD lasts for 30 years or more. Yet the most commonly used model systems for
studying the disease have lifespans of only a few weeks (cultured neurons) to 2-3 years
(transgenic mice). Researchers do not know how to reconcile the results of the relatively
short term experiments in these systems to the decades-long disease course. Furthermore,
there is no “mouse model of Alzheimer’s disease” that reproduces all of the cardinal
features of the human disease: amyloid plaques, neurofibrillary tangles, and most
importantly, widespread neuron loss. Developing such a model is one of the most urgent
priorities in the field.
Despite these challenges, scientists have made significant advances toward
understanding the etiology of AD. One of the most important insights is that plaques and
tangles are themselves unlikely to be toxic to neurons; rather, these lesions are indications
of abnormal processing of Aβ and tau. Identification of the pathogenic forms of these
proteins and their molecular targets should allow us to define the pathways through
which they exert their toxicity. The ultimate validation of any proposed mechanism must
come from studies of the actual disease in human subjects – testing whether interventions
that block putative harmful processes, or promote protective processes, prevent dementia
in people at risk for AD.
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