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Commentaries |
From the Department of Pathology and Laboratory Medicine, Divisionof Anatomical Pathology, University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania
Although fibrillar Aß
deposits in the extracellular space, known as senile plaques (SPs), and
intraneuronal aggregates of 
fibrils, known as neurofibrillary
tangles (NFTs), exhibit properties of amyloid and are the defining
neuropathological hallmark lesions of the Alzheimer’s disease (AD)
brain, most patients with familial or sporadic forms of AD as well as
elderly Down’s syndrome patients with AD also exhibit a third type of
amyloid lesion, known as a Lewy body (LB), which is formed by
intraneuronal accumulations of 
-synuclein fibrils.1-3
Thus, AD is a neurodegenerative dementia in which clinical
manifestations may arise from a triplet of brain amyloidoses caused by
the pathological fibrillization of at least three different building
block peptides or proteins (ie, Aß, , and -synuclein) that form
three distinct types of amyloid deposits (ie, SPs, NFTs, and LBs,
respectively) within or outside neurons. However, there are a host of
other pathologies that also are consistently associated with AD brain
degeneration including neuron and synaptic loss, gliosis, microglial
proliferation, as well as other evidence of inflammatory processes,
oxidative/nitrative damage, lipid peroxidation, and cholinergic
deficits.4
Although a direct causal or mechanistic link
between these other abnormalities and the diagnostic hallmark SPs and
NFTs of AD remain primarily speculative, several of these pathological
processes (eg, inflammation and cholinergic deficits) have emerged as
potential targets of therapeutic intervention in AD.5-8
Indeed, the first Food and Drug Administration-approved AD-specific
therapies were directed at correcting the cholinergic neurotransmitter
abnormalities in AD, and, although later generation cholinesterase
inhibitors have less toxicity than the original prototype compound, the
therapeutic efficacy of this class of drugs has been modest at best to
date.6,7
Thus, further progress toward optimizing this
therapeutic strategy for the treatment of AD patients, as well as
further insights into the role of cholinergic neurotransmitter failure
in the cognitive and other clinical impairments in AD could benefit
from studies of the cholinergic system in animal models of AD-like
neuropathology.
To that end, in the current issue of The American Journal of
Pathology, Gau and colleagues9
report studies
examining presynaptic cholinergic markers and ß-secretase activity
during the progressive accumulation of AD-like Aß amyloidosis in one
of the most well-characterized transgenic mouse models of this
neuropathology (Tg2576 mice), which was established by Hsiao and
collaborators10
by engineering these mice to
overexpress the human amyloid precursor protein (APP) with the Swedish
double familial AD (FAD) mutation (APPswe). Indeed, these mice show
many features of AD-like neuropathology including such abnormalities as
SPs and other forms of Aß deposits, increased levels of soluble and
insoluble Aß, abnormal synaptic plasticity, microgliosis,
inflammation, oxidative stress, lipid peroxidation, and so
forth.10-18
Further, although they do not develop NFTs or
LBs, these transgenic mice do show evidence of , ubiquitin, and
-synuclein-positive neurites similar to those seen in AD
brains,19
but, in remarkable contrast to the AD brain, the
Tg2576 mice show little or no neuron loss in the central nervous
system, even at the end of their life span when SPs, other Aß
deposits, and brain Aß peptides are highly abundant.20
Thus, these transgenic mice recapitulate most of the features of the
Aß amyloidosis typical of classic AD, thereby making them attractive
animal models for many types of studies of degenerative processes in
AD, as well as for the screening and testing of anti-Aß amyloid
therapies, but they do not show extensive verisimilitude to the full
spectrum of AD neurodegenerative pathology. Moreover, in the studies of
these mice at 14, 18, and 23 months of age conducted by Gau and
colleagues9
reported herein, the authors noted that there
were no significant differences between wild-type and transgenic mice
with respect to four separate measures of central nervous system
cholinergic neurotransmission, ie, choline acetyltransferase and
acetylcholinesterase activities, binding to vesicular acetylcholine
transporter and Na+-dependent high-affinity
choline uptake sites. Although an enzyme-linked immunosorbent assay
designed to measure the secreted human ß-secretase cleavage product
(APPsßswe) of APPswe did not demonstrate any abnormalities with aging
in the brains of these transgenic mice, Gau and
colleagues9
did detect an age-dependent increase in
soluble Aß40 and Aß42 levels and progressive deposition of Aß
into SPs and other plaque-like lesions, and these findings are
primarily consistent with those described in several earlier
reports.10,14,15,17
Based on their findings of presynaptic
cholinergic integrity in aging Tg2576 mice, Gau and
colleagues9
suggest that these mice may show more
verisimilitude to the early stages of AD with preserved presynaptic
cholinergic innervation rather than to fully developed or end stage AD.
Nonetheless, the authors point out that some lines of transgenic mice
that model AD amyloidosis do show evidence of a certain degree of
cholinergic abnormalities.21-23
However, among the large array of pathological abnormalities seen in
the AD brain, it seems increasingly likely that brain amyloidosis is
the driving force underling the neurodegeneration and clinical
impairments in AD. Accordingly, it would seem highly plausible that the
well-documented cholinergic deficits in AD could be because of deposits
of amyloid formed from and/or -synuclein fibrils, if they are
not caused by deposits of fibrillar Aß amyloid. Indeed, recognition
of a common mechanistic theme shared by AD and many other seemingly
unrelated neurodegenerative disorders (eg, synucleinopathies,
tauopathies, prion disorders, trinucleotide repeat diseases) has begun
to emerge with the growing realization that a large number of these
disorders are characterized neuropathologically by intracellular and/or
extracellular aggregates of proteinaceous fibrils many of which show
the properties of amyloid including thioflavin staining as well as
Congo Red birefringence.1
Thus, these disorders may share
similar physicochemical targets for drug discovery, and despite
differences in the molecular composition of the structural elements of
these filamentous amyloid lesions, an expanding body of evidence
supports the hypothesis that similar pathological mechanisms (ie,
aberrant protein folding, fibrillization, and aggregation) may underlie
all of these disorders. Specifically, the onset and/or progression of
neurodegeneration in AD and other degenerative disorders characterized
by prominent brain amyloidosis may be linked mechanistically to
abnormal interactions between brain proteins that lead to their
assembly into filaments and the aggregation of these filaments within
and/or outside brain cells as fibrous amyloid deposits.1
These filamentous lesions are exemplified by NFTs as well as SPs in
sporadic and familial AD. Moreover, although LBs are regarded as
hallmark intracytoplasmic neuronal inclusions of Parkinson’s disease,
they also occur in the most common subtype of AD known as the LB
variant of AD, and it is now known that FAD mutations and trisomy 21
lead to abundant accumulations of LBs composed of -synuclein
filaments in the brains of most FAD and elderly Down’s syndrome
patients, respectively.1-3
Thus, the aggregation of brain
proteins into potentially toxic lesions is emerging as a common
mechanistic theme in a diverse group of neurodegenerative diseases that
share an enigmatic symmetry, ie, missense mutations in the gene
encoding the disease protein cause a familial variant of the disorder
as well as its hallmark brain lesions, but the same brain lesions also
can be formed by the corresponding wild-type brain protein in a
sporadic form of the disease. Thus, clarification of this enigmatic
symmetry in any one of these disorders is likely to have a profound
impact on understanding the mechanisms that underlie all of these
disorders as well as on efforts to develop novel therapies to treat
them. Nonetheless, because most progress in the last decade of AD
research has been made toward identifying therapeutic targets to
prevent or eliminate amyloid deposits formed by Aß fibrils, many of
the most promising emerging therapies for AD have been or are directed
at these targets.8
For example, as described
elsewhere8
and in the Alzheimer Research Forum website
(http://www.alzforum.org), there is a growing number
of proposed potential AD therapies that target the disruption of
filamentous Aß lesions in the AD brain or they are designed to
prevent formation of them, and it is possible that similar principles
could be exploited to treat other forms of brain amyloidosis. Indeed,
it is now feasible to screen large libraries of compounds in
high-throughput in vitro assays to identify small numbers of
drugs that then can be selected for more focused testing in animal
models of neurodegenerative diseases.24
Moreover, novel
therapeutic approaches that use peptide building blocks of the abnormal
fibrils that form brain deposits of Aß amyloid in AD as vaccines to
prevent or reverse AD amyloidosis8
could be extended to
treat other neurodegenerative disorders characterized by brain
amyloidosis, and, quite remarkably, this seems plausible to accomplish
even for a seemingly intractable group of diseases such as prion
disorders.25
However, the availability of transgenic mice that model multiple brain
amyloidoses (due for example to Aß, , and -synuclein fibrils
versus only one form of amyloidosis resulting from the
fibrillization of only a single fibrillizing peptide/protein) should
enhance efforts to develop more specific therapies for the different
forms of amyloid in AD brains.26,27
Indeed, one might
envision the generation of transgenic mice that separately model Aß
amyloidosis, amyloidosis, and -synuclein amyloidosis, as is
currently the case, as well as other transgenic mice that model all
three of these amyloidoses, similar to the LB variant of AD, or
transgenic mice with admixtures of these various amyloids to model AD
without LBs or tauopathies with some Aß deposits such as Marianna
Island dementia, and so forth. Additionally, these mouse model systems
will prove exceptionally valuable in dissecting out the molecular and
cellular mechanisms that lead to cholinergic deficits in AD. Finally,
whether or not the interpretations and speculations by Gau and
colleagues9
of their current findings prove to be fully
correct, it is increasingly clear that neuropathological verisimilitude
of animal models of AD to the entire spectrum of AD brain degeneration
(ie, from the prodromal to the end stages of this disorder) will
provide the necessary model systems with which investigators can
dissect out the entire cascade of cellular and molecular pathways that
underlie AD brain degeneration. With these models in hand, it also
should be possible to develop an array of therapeutic interventions
that might benefit patients regardless of where they lie along the AD
neurodegeneration continuum.
Footnotes
Address reprint requests to Dr. John Q. Trojanowski, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, 3rd Floor Maloney Bldg., 3600 Spruce St., Philadelphia PA, 19104-4283. address: trojanow{at}mail.med.upenn.edu; Website address:
Supported by grants from the National Institute on Aging, National Institutes of Health, and the Alzheimer’s Association.
Accepted for publication November 30, 2001.
References
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