Views & Reviews
A focus on the synapse for
neuroprotection in Alzheimer
disease and other dementias
Paul Coleman, PhD; Howard Federoff, MD, PhD; and Roger Kurlan, MD
Abstract—Synaptic dysfunction and failure are processes that occur early in Alzheimer disease (AD) and are important
targets for protective treatments to slow AD progression and preserve cognitive and functional abilities. Synaptic loss is
the best current pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and
neurons are lost. Once synaptic function fails, even in the setting of surviving neurons, there may be little chance of
effectively interfering with the disease process. This review emphasizes the importance of preserving synaptic structure
and function (i.e., “synaptoprotection”) in AD. Such “synaptoprotective” therapy will probably need to be administered at a
critical early time point, perhaps years before onset of clinical symptoms.
Alzheimer disease (AD) and related dementias are
neurodegenerative conditions characterized by progres-
sive brain dysfunction occurring in an apparently
staged cell biologic sequence: neuronal injury, synaptic
failure, and neuronal death. Recent advances in eluci-
dating the underlying molecular pathogenic mecha-
nisms have suggested the possibility for novel
therapeutic approaches. One such treatment strategy
would target pathogenic pathways upstream of neuro-
nal death. Whether or not this will be an effective
disease-modifying paradigm is the subject of conjec-
ture. A compelling case, however, can be made for ear-
lier intervention (i.e., at the stage of neuronal injury or
synaptic failure but prior to neuronal death).
Accumulating evidence indicates that cognitive
deficits may be detected well before a clinical diagno-
sis of AD is reached. For example, Kawas et al.,1
reporting deficits in visual memory, suggest “that
the disease process may already be occurring de-
cades before clinical symptoms appear.” Similarly,
study of the Framingham cohort led to the conclu-
sion that lower scores in abstract reasoning and re-
tention preceded a clinical diagnosis of probable AD
by 10 years.2Although imaging studies suggest that
the onset of medial temporal lobe atrophy antedates
the diagnosis of dementia by 3.5 years in familial
AD,3atrophy does not appear to be sufficient to ac-
count for the long prodromal period. What, then,
may be the neurobiologic substrate of the declines
that predict a diagnosis of AD?
A series of prospective clinicopathologic studies in-
volving patients with AD performed over the last two
decades found a consistently poor correlation between
the degree of cognitive impairment and the severity of
the characteristic neuropathologic features of AD, in-
cluding neuronal loss, amyloid plaques, and neurofi-
brillary tangles (NFTs). By contrast, the extent of
synaptic loss has been found to be an excellent corre-
late of dementia, accounting for about 50% of the mea-
sured variance.4-7More recently, synaptic loss has been
shown to be the best pathologic correlate of cognitive
decline in other dementias, including frontotemporal
dementia8and dementia with Lewy bodies,9,10as well
as normal aging.11,12
This article will review emerging scientific evidence
pointing to the synapse as an appropriate target for
early diagnosis and potential experimental therapeutic
interventions to slow AD progression and preserve cog-
nitive and functional abilities. We present evidence
that well before neurons die in the AD brain, they go
through a sequence of synaptic changes that compro-
mise the functional capacity of neuronal networks that
lead, eventually, to the cognitive deficits of AD. The
synaptic changes include not only the loss of syn-
apses13,14but also impaired capacity of still-existing
synapses. We review data indicating that these synap-
tic changes begin prior to the appearance of the neuro-
nal loss, plaques, and NFTs that constitute the classic
neuropathologic definition of disease. As these synaptic
failures of AD are found in advance of current neuro-
From the Department of Neurology (Drs. Federoff and Kurlan) and Center for Aging and Developmental Biology (Drs. Coleman, Federoff, and Kurlan),
University of Rochester School of Medicine, NY.
Received August 14, 2003. Accepted in final form April 12, 2004.
Address correspondence and reprint requests to Dr. R. Kurlan, University of Rochester School of Medicine, 601 Elmwood Ave., Rochester, NY 14642-8673;
Copyright © 2004 by AAN Enterprises, Inc.
pathologic markers of disease and also prior to clinical
detection of disease, we argue that there is a need for
the explicit recognition that AD starts long before the
appearance of the traditional ways of detecting the ill-
ness. These facts lead us to conclude that the optimal
treatment of AD must be aimed at events well in ad-
vance of neuronal death, targeting mechanisms that
disrupt synaptic function.
Synaptic pathology in AD.
indications of synaptic malfunction in AD comprised
data demonstrating decline of acetylcholine neuro-
transmitter content in AD.5,15,16These data have pro-
vided the foundation of the currently used cholinergic
medications. Although this type of therapy is helpful to
some for a limited time, it is unclear whether cholin-
ergic drugs alter the basic course of disease.
Many studies have demonstrated decreased den-
sity of synapses in a variety of regions in the AD
brain. As the methods used in these studies show a
decrease in synaptic density, they probably underes-
timate the degree of loss of synapses in AD. If we
combine reduced synaptic density with the shrinkage
of parenchyma in AD, then the true synaptic loss is
almost certainly greater than the density data alone
indicate. The degree of synaptic loss in AD is uneven,
the frontal cortex being most and the occipital cortex
least affected.17,18The most prominent reduction of
synapses is found in the outer parts of the molecular
layer of the dentate gyrus,19-21probably as a conse-
quence of reduced entorhinal input. Within the
dense amyloid core of a classic senile plaque, syn-
apses are completely lost.21
Synaptic dysfunction or loss contributes to clinical
signs of dementia by the apparent disruption of neu-
ronal communication. Even structurally intact-
appearing synapses may be dysfunctional. This could
arise from defects in transmitter synthesis, trans-
port, release, and reuptake, disturbed vesicle traf-
ficking,22,23altered or reduced transmitter receptors,
transporters, pumps, and ion channels, and defects
in second messenger systems.24Dysfunction of syn-
apses has also been associated with downstream pro-
cesses that may be linked to the neurodegenerative
process and clinical decline, including reduction in
metabolic activity and regional cerebral blood flow,25
activation of microglia,26and loss of nicotinic
In AD, many living neurons are diseased and los-
An important recent observation indi-
cates that synaptic function can be lost for a neuron
that remains “living.” In our own histopathologic stud-
ies of single neurons in postmortem brains, we have
defined two criteria for a live neuron: 1) It must con-
tain a nucleus, and 2) it must contain intact messenger
RNA (mRNA). We found that many neurons from AD
brains that satisfy the above dual criteria are neverthe-
less diseased and have been so for a long time. Obser-
vation of tissue routinely prepared from AD brain
reveals a large number of neurons containing both in-
tact nuclei and NFTs. These neurons are also still gen-
One of the earliest
erating transcripts that can be demonstrated by in situ
hybridization or other methods28,29and can thus be con-
sidered alive. The existence of large numbers of such
immunocytochemically abnormal neurons in selected
regions of postmortem brain suggests that neurons
may be surviving in this state for long periods of time.
In fact, enumeration of live neurons containing NFTs
can be linked with data on numbers of neurons and
neuronal loss as a function of age (time) in AD30,31to
indicate that, on average, neurons survive for decades
after they have formed NFTs.32Thus, although these
neurons remain alive, they have sustained injury for
decades. At a structural level, the neuronal cytoskel-
etal apparatus has been disrupted,33and the dendritic
tree has been pruned.34,35Molecular changes have also
been found in these neurons, particularly involving
proteins responsible for synaptic function.36-38The time
scale for this alive but diseased state may be extended
further by the findings that molecular changes indica-
tive of disease precede the formation of frank
NFTs.36,39,40Thus, diseased neurons in AD survive for
long periods during which their structure and function
Although it is obvious that the death of neurons in
AD30,41must be one factor in the synaptic reduction
in this disease, there are data indicating additional
contributions to this loss. Quantitative analysis of
the density of neurons and synapses in temporal and
frontal neocortex in AD has demonstrated a decrease
in the synapse to a neuron ratio up to 48%.42Such
data suggest that although a significant percentage
of the loss of synapses in AD may be due to the death
of the neurons forming synapses, an additional
source of synaptic loss in AD comes from still viable
Where does synaptic pathology start?
There has been no systematic survey of brain regions
aimed at defining the locus of earliest loss of synapses,
let alone the molecular/cellular changes that precede
detectable synaptic loss. However, as both pathologic43
and clinical evidence converge to suggest earliest in-
volvement of the transentorhinal/entorhinal cortex re-
gion critical for recent memory, we suggest that it may
be the cells in this region that show the earliest mani-
festations of synaptic pathology. On the other hand, it
has been pointed out that some of the very earliest
clinical signs of AD (personality change, reduced spon-
taneity, word-finding problems, difficulties with calcu-
lation) are most consistent with widespread neocortical
changes despite the fact that the earliest identifiable
AD pathology occurs in the limbic entorhinal cortex.
Early degeneration of neocortical synapses has been
proposed to explain this contradiction in clinicopatho-
Cellular. Dendrites make up ?90% of the sur-
face that many neurons offer for synaptic contact,45
and as much of the dendritic extent is distant from
the supportive functions of the cell body, it is not
surprising that incipient degenerative processes
would begin there and disrupt synaptic function
early. It has been more than two decades since Buell
October (1 of 2) 2004
and Coleman’s original observations34that surviving
cortical neurons expand their dendritic trees in nor-
mally aging brain, but that this plastic capacity is
decreased in the AD brain. These studies showed
that the major decrements of the dendritic tree were
in the more distal, terminal dendrites. Similarly, E.
Braak et al.33have shown that the degenerative pro-
cess starts in the distal dendrites prior to the ap-
pearance of frank NFTs. These dendritic losses in
AD apparently parallel synaptic decrements as sug-
gested by quantitative morphometric studies show-
ing that major loss of synapses is evident in the early
stages of AD.18,46Synaptic loss precedes the decre-
ment of choline acetyltransferase activity in AD as
assessed in postmortem brains.47
That synapses may fail even in the presence of
viable neurons highlights the fact that a protective
treatment aimed at preserving neurons may inter-
vene too late in the pathologic process. Once synaptic
function fails, even in the setting of surviving neu-
rons, the “horse is out of the barn,” and there may be
little chance of effectively interfering with the dis-
ease process. This analysis underscores the impor-
tance of preserving synaptic structure and function
(“synaptoprotection”) and emphasizes that early in-
tervention should be directed toward the pathoana-
tomic entity most closely linked to clinical course.
Mechanisms of synaptic pathology.
operation of synapses requires the coordinated action
of large numbers of gene products that serve not only
to form the pre- and postsynaptic membrane com-
plexes but also to synthesize and deliver a multitude
of mRNAs and proteins to appropriate sites. Thus,
transmitters must be synthesized, posttranslation-
ally processed, and transported, and the protein com-
plexes that form receptors must be synthesized
(some of them locally) and appropriately assembled
and inserted into membrane. Vesicle trafficking, in-
cluding reuptake and vesicle assembly, must be ac-
complished in appropriate balance with synthesis
and release of transmitter. The mechanisms that co-
ordinate the release of transmitter in response to
arrival of the electrical impulse must be intact, as
must the second messenger systems that propagate
information from the receptor. And the energetics
that all these actions require must be supplied. So,
what goes wrong in AD in this complex molecular
In spite of the large body of accumulating knowl-
edge regarding cellular and molecular mechanisms
of synaptic function,24,48understanding of the com-
plex mechanisms by which synaptic structure and
function are disrupted in AD remains significantly
incomplete. One aim of the preceding discussion of
synaptic decline in AD has been to paint a picture of
progressive decline. The elements we have consid-
ered have included decreased capacity to recycle syn-
aptic vesicles, loss of synapses by still-living
neurons, and, finally, loss of synapses by the death of
neurons forming those synapses—probably taking
place in this order within a given single cell. Cer-
tainly, the deficits in transmitter systems and ener-
getics characteristic of AD also play significant roles
at some point in the progressive decline of synaptic
structure and function. However, the point at which
they become significant is uncertain, and as such we
have not addressed these herein.
A number of studies have focused on defective pro-
cessing of amyloid precursor protein (APP) as con-
tributing to early synaptic damage. Studies in
transgenic animals indicate that APP participates in
synaptic stabilization and that abnormal metabolism
of this molecule might cause synaptic dysfunction,49
perhaps by a direct toxic effect of amyloid ?-protein
(A?) on synapses.50-52A recent study involving trans-
genic mice that overexpress human mutant APP found
evidence of hippocampal atrophy even before the depo-
sition of A? that occurs in these animals.53The binding
of A? to agrin, a molecule that promotes dendritic
branching, is suggested to be critical to synaptic failure
in AD. Translocation of the C-terminal fragment of
APP to the neuronal nucleus has been shown to cause
critical changes in DNA transcription that may modu-
late expression of gene products critical to synaptic
function.54These results suggest that disturbances in
APP processing initiate pathologic changes, probably
involving synapses, early on, prior to the formation of
plaques, and emphasize the importance of early
A disturbance of synaptic proteins has been con-
sidered for some time,55and recent studies have
identified in AD reductions of a variety of proteins
playing a role in synaptic structure, synaptic vesicle
trafficking, and synaptic plasticity. One study found
that protein markers for presynaptic vesicles, presyn-
aptic membrane, and postsynaptic components were
concordantly reduced in early-onset AD, suggesting
early loss of the entire synaptic apparatus rather than
specific parts.56We and others have found a reduction
in the levels of synaptophysin in AD, particularly in
neurons containing NFTs.19,20,38,57,58A recent study has
confirmed that loss of synaptophysin, particularly in
frontal cortex, is an early event in AD.18More recent
studies also suggest that synaptic vesicle functioning
may be among the earliest targets of AD. For example,
both GTPase dynamin and AP180 play a role in synap-
tic vesicle trafficking, and both have been found to be
reduced early in AD.22,23,59,60Loss or malfunction of the
machinery for synaptic vesicle trafficking could result
in the synaptic dysfunction that appears to occur early
in AD. In support of this possibility, APP transgenic
mice show changes in the expression of several genes
related to synaptic vesicle exo/endocytosis and im-
paired learning, even before evident structural destruc-
tion or loss of synapses.61
Other components of the picture are emerging.
Certainly, the cytoskeletal disruption associated
with the formation of NFTs has detrimental effects
on transport with consequences for synapses.38,57The
microtubule disruption associated with abnormal tau
October (1 of 2) 2004
phosphorylation62,63also has been associated with de-
creased expression of selected synapse-associated
gene products even in the absence of NFTs.40
Whether this association represents direct causality
or other concomitant factors remains unproven.
However, these data suggest that therapeutic modu-
lation of tau phosphorylation at known sites may be
of therapeutic value in AD.
Recent studies suggest a pathogenic process link-
ing a number of elements in the picture of synaptic
decline in AD. Their evidence points to a cascade in
which a soluble APP C-terminal fragment leads to
interleukin-1 mediating an host of neuronal/glial re-
actions including 1) increased acetylcholinesterase
expression and activity,642) increased tau phosphor-
ylation at an AT8 epitope,263) decreased synapto-
function.65Their data indicate that at least some of
these responses may be produced through a p38-
mitogen activated protein kinase pathway that medi-
ates tau phosphorylation and synaptic effects.26In
addition, they show that the proinflammatory re-
sponses of microglia are modulated more effectively
by ApoE3 relative to ApoE4.66Although these data
do not encompass the entirety of mechanisms of syn-
aptic failure in AD, they underscore important com-
ponents of AD changes leading to synaptic decline.
Potential therapeutic approaches to protect syn-
apses can be viewed in the context of current data on
the potential initiating mechanisms of synaptic dys-
function and loss in AD. There are a variety of fac-
tors that can reasonably be considered as causative.
We have reviewed evidence pointing to APP as hav-
ing an important role. Recent attention has focused
on APP peptides, especially oligomeric A?-derived
diffusible ligands (ADDLs).67ADDLs increase in AD
brain and attach to neurons in vitro,68block long-
term potentiation (LTP),69and cause cell death.70
The ability to diminish LTP certainly suggests inter-
ference with synaptic function, although the details
of the mechanism by which this might be accom-
plished are currently uncertain.
in microglia with
Initiation of synaptic pathology: When does it
There is no question that synaptic pathology
begins well in advance of the appearance of AD clin-
ical symptoms. Can we date the likely time of onset
of AD? Postmortem neuropathologic studies have
demonstrated that classic AD pathology is identifi-
able in a substantial number of brains from individ-
uals with no known cognitive decline. In this study,
close to 20% of persons who died in their 20s had AD
pathology.71It is not until the mid-70s that 20% of a
sample population has progressed to clinically diag-
nosed AD, suggesting a decades-long process of brain
and synapse deterioration. Do persons with neuro-
pathologic stigmata of AD, even though it is not yet
detected clinically, have the disease? They probably
do. Evidence suggests that such persons may be con-
sidered to have AD even in advance of the classic
neuropathologic stigmata of the disease. For exam-
ple, Redwine et al.53convincingly demonstrated re-
duced volume of the molecular layer of the dentate
gyrus by 100 days of age in the PDAPP transgenic
mouse model of AD. A?-containing plaques have
been shown to accumulate in this model by 240 to
300 days. It is reasonable to argue that the volumet-
ric change preceding the appearance of plaques rep-
resents loss of dendritic and synaptic structure.
Thus, this observation is seminal in demonstrating
structural change antedating the appearance of one
of the traditional markers of AD pathology.
The study of Redwine et al.53is evidence support-
ing the conclusion that in AD, the appearance of
senile plaques and NFTs is a late event in the dis-
ease’s pathologic cascade. The disease process, in-
cluding synaptic loss72and neuronal dysfunction,36,73
as well as possible loss, appears to be well on its way
prior to demonstration of the characteristic neuro-
pathologic features. Other studies of AD animal
models have demonstrated behavioral and morpho-
logic losses in the absence of plaques.74Similarly, it
has been shown that altered posttranslational pro-
cessing of tau is found prior to the formation of
NFT75and that these changes have functional conse-
quences for microtubule integrity62,63and the expres-
sion of synaptic molecules.40Now that we know that
plaques and tangles are neuropathologic latecomers,
it is clear that, at least for some persons, the disease
process may begin in the teenage years or earlier.
Supporting this conclusion may be the finding that
young nuns destined for AD had deficient linguistic
function compared with their peers who did not de-
ment in later life, although this observation might be
explained by differences in level of education.76Al-
though advancing age appears to be a critical factor in
the evolution of AD, synaptic preserving therapy will
likely be most effective if initiated in the very earliest
stages of illness. For AD, this is probably decades prior
to the first clinical signs of dementia. This information
highlights the critical need to identify accurate genetic
and other biomarkers of increased disease risk and of
early synaptic dysfunction in presymptomatic
tic dysfunction is an early process in AD, that this
pathologic process appears to be the one most closely
linked to clinical decline, and that synapses may be
dysfunctional even in surviving neurons, there is
reason for optimism in focusing on the synapse as
the most appropriate target of experimental thera-
peutics. The reason is that synapses appear to have
a remarkable capacity to respond to and compensate
for a variety of neurobiologic stressors. This synaptic
plasticity might be taken advantage of to limit or
slow the neurodegenerative process in AD and other
It has long been known that axons have a remark-
able plastic capacity to reinnervate and form syn-
apses on CNS sites that have been denuded of
Despite evidence that synap-
October (1 of 2) 2004
synaptic input. The principle of neuronal plasticity
in response to lesions of the mature mammalian
CNS had been well established by the 1960s by ani-
mal studies.77Subsequently, Cotman et al.78,79
started a series of investigations into the details of
neuronal/synaptic plasticity in the mammalian hip-
pocampus. One of the pertinent findings of their
studies was that the aged rodent brain continued to
retain the capacity for plastic synaptogenesis in the
dentate gyrus molecular layer in response to le-
sions.80Additionally, the morphologic indicators of
neuronal plasticity in the rodent brain have been
shown to be behaviorally and physiologically signifi-
cant.81Demonstration of neuronal plasticity was ex-
tended to the aged human CNS by the quantitative
Golgi studies of Coleman et al.34,82
Unfortunately, although synaptic plasticity may
serve as a productive avenue for protective therapies,
there is also evidence that processes involved in plas-
ticity of the synapse are disturbed in AD, and this may
be a critical factor limiting appropriate neuronal re-
sponses to disease-related neurobiologic stresses. Pro-
teins involved in synaptic plasticity, including growth-
associated protein 43 (GAP-43),28the postsynaptic
actin binding protein drebrin,83and synaptophysin,4,40
have been reported to be reduced in AD. One author
proposed that the defect of cholinergic neurotransmis-
sion that characterizes AD may perpetuate the patho-
logic process as acetylcholine plays a critical role in
regulating synaptic modeling.84
However, in spite of these indications of reduced
plasticity in the AD brain, there are also a number of
demonstrations of residual plastic capacity in the AD
brain. These include evidence of sprouting of cholin-
ergic fibers in the molecular layer of the dentate gy-
rus,85increased size of synapses in regions with
synaptic loss,86increased expression of GAP-43 mes-
sage in early AD,87and localized GAP-43 immunoreac-
tivity.88Additionally, studies have shown reactive
synapse formation, enlargement of synaptic contact ar-
eas, increase in the area of single synaptic junctions, as
well as synaptic perforations and splitting.7,89-93
Recent work suggests that neurotrophins such as
nerve growth factor (NGF) and brain-derived neuro-
trophic factor (BDNF) may be more than a develop-
mental survival factor for neurons. They appear to
have key roles in regulating synaptic plasticity.94-124In
support of this function, both neurotrophins are re-
leased in an activity-dependent manner.101,105,125-128Re-
cent work highlights a new aspect of neurotrophin
biology. Synthesized as pre-pro-polypeptides, NGF and
BDNF are typically cleaved to mature molecules prior
to secretion. Interestingly, pro-NGF can be secreted
and preferentially binds to the pan-neurotrophin recep-
tor p75 rather than TrkA.129This ligation event pro-
motes a cell death instead of a survival signal.
Extracellular proteolytic processing of pro-NGF could
liberate mature NGF and accordingly change the sign
of its synaptic action. The BDNF gene has a rare poly-
morphism within its pro-region that results in a valine-
to-methionine codon change that impairs pro-hormone
cleavage.126This polymorphism occurs with greater fre-
quency in patients with AD and other neurologic disor-
ders. NGF is present in hippocampus on the
postsynaptic side of hippocampal neurons, and its ex-
pression and release are regulated by depolarization
and presumably synaptic activity.127,128Neurons main-
tain two pools of NGF: a constitutive pool in the soma
that may be the one maintaining survival and a regu-
latable pool in the dendrites that responds to synaptic
activity127,128(H. Federoff, unpublished observations).
Small changes in NGF expression can in transgenic
mice alter synaptic relationships and modify learning
and memory functions.130-132NGF has been localized to
the postsynaptic density in cultured hippocampal neu-
rons (H. Federoff, unpublished observations). Possible
disturbances of BDNF or NGF processing or function
in synaptic plasticity should be more closely examined
in AD and other dementias.
correlate of cognitive decline in AD and other demen-
tias. Synaptic dysfunction is an early event in AD
and appears to predate neuronal loss. This is not
surprising as dendrites constitute a large portion of
the neuronal surface area. Because of its distance
from the soma, the synaptic region may be particu-
larly vulnerable to processes that disrupt intracellu-
lar signaling and axonal transport, which appear to
occur in the degenerative dementias. A variety of
mechanisms appear to contribute to synaptic failure,
including disturbances of synaptic proteins, mem-
brane lipids, vesicular function, and loss of plasticity
functions. Excitotoxicity, oxidative stress, and apo-
ptosis may be involved. In AD, the initiating events
in synaptic dysfunction may be direct toxic effects of
A? and disrupted intracellular transport by aggre-
Certainly, the death of a neuron results in the loss
of those remaining synapses made by this cell. How-
ever, to focus exclusively on saving the neuron ig-
nores the loss and malfunction of the synapses of
still-living neurons. We have reviewed data indicat-
ing that still-living neurons lose synapses and that
this loss may represent as much as 38% of the total
synaptic loss in AD. In addition, even those synapses
that are still structurally present may be malfunc-
tioning by virtue of defects in transmitter systems,
energetics, vesicle trafficking, and other critical pro-
cesses. It is clear that successful protective therapy
aimed at slowing or preventing disease progression
of the dementias must preserve synaptic function.
Such therapies must be administered at a critical
early time point because synaptic failure may be
among the earliest changes. Tardy intervention that
prolongs neuronal survival after synaptic demise has
occurred may be futile. It is likely that synaptic dys-
function begins decades prior to onset of clinical
symptoms so that such “synaptoprotective” therapies
must be administered as early as possible, probably
in presymptomatic individuals, to have optimal ben-
efits. As discussed above, recent research has sug-
Synaptic loss is the best pathologic
October (1 of 2) 2004
gested a number of synaptic structures and functions
that are disturbed early in dementing illnesses and
may serve as good targets for identifying early bi-
omarkers and rational “synaptoprotective” therapies.
The future promise of such “synaptoprotective”
agents may lead to an unprecedented alteration in
the natural history of AD.
1. Kawas CH, Corrada MM, Brookmeyer R, et al. Visual memory predicts
Alzheimer’s disease more than a decade before diagnosis. Neurology
2. Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino RB. The
preclinical phase of Alzheimer disease: a 22-year prospective study of
the Framingham Cohort. Arch Neurol 2000;57:808–813.
3. Schott JM, Fox NC, Frost C, et al. Assessing the onset of structural
change in familial Alzheimer’s disease. Ann Neurol 2003;53:181–188.
4. Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive
alterations in Alzheimer’s disease: synapse loss is the major correlate
of cognitive impairment. Ann Neurol 1991;30:572–580.
5. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in
Alzheimer’s disease. Lancet 1976;2:1403.
6. Samuel W, Masliah E, Hill LR, Butters N, Terry R. Hippocampal
connectivity and Alzheimer’s dementia: effects of synapse loss and
tangle frequency in a two-component model. Neurology 1994;44:2081–
7. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in
Alzheimer’s disease: correlation with cognitive severity. Ann Neurol
8. Lipton AM, Cullum CM, Satumtira S, et al. Contribution of asymmet-
ric synapse loss to lateralizing clinical deficits in frontotemporal de-
mentias. Arch Neurol 2001;58:1233–1239.
9. Masliah E, Mallory M, DeTeresa R, Alford M, Hansen L. Differing
patterns of aberrant neuronal sprouting in Alzheimer’s disease with
and without Lewy bodies. Brain Res 1993;617:258–266.
10. Brown DF, Risser RC, Bigio EH, et al. Neocortical synapse density and
Braak stage in the Lewy body variant of Alzheimer disease: a compar-
ison with classic Alzheimer disease and normal aging. J Neuropathol
Exp Neurol 1998;57:955–960.
11. Tigges J, Herndon JG, Rosene DL. Preservation into old age of synap-
tic number and size in the supragranular layer of the dentate gyrus in
rhesus monkeys. Acta Anat (Basel) 1996;157:63–72.
12. Uylings HB, de Brabander JM. Neuronal changes in normal human
aging and Alzheimer’s disease. Brain Cogn 2002;49:268–276.
13. Selkoe D. Alzheimer’s disease is a synaptic failure. Science 2002;298:
14. Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuro-
pathol Exp Neurol 2000;59:1118–1119.
15. Bowen DM, Benton JS, Spillane JA, Smith CC, Allen SJ. Choline
acetyltransferase activity and histopathology of frontal neocortex from
biopsies of demented patients. J Neurol Sci 1982;57:191–202.
16. Perry E. Acetylcholine and Alzheimer’s disease. Br J Psychiatry 1988;
17. Clinton J, Blackman SE, Royston MC, Roberts GW. Differential syn-
aptic loss in the cortex in Alzheimer’s disease: a study using archival
material. Neuroreport 1994;5:497–500.
18. Masliah E, Mallory M, Alford M, et al. Altered expression of synaptic
proteins occurs early during progression of Alzheimer’s disease. Neu-
19. Hamos JE, DeGennaro LJ, Drachman DA. Synaptic loss in Alzhei-
mer’s disease and other dementias. Neurology 1989;39:355–361.
20. Honer WG, Dickson DW, Gleeson J, Davies P. Regional synaptic pa-
thology in Alzheimer’s disease. Neurobiol Aging 1992;13:375–382.
21. Lassmann H, Fischer P, Jellinger K. Synaptic pathology of Alzhei-
mer’s disease. Ann NY Acad Sci 1993;695:59–64.
22. Yao PJ, Coleman PD. Reduced O-glycosylated clathrin assembly pro-
tein AP180: implication for synaptic vesicle recycling dysfunction in
Alzheimer’s disease. Neurosci Lett 1998;252:33–36.
23. Yao PJ, Zhu M, Pyun EI, et al. Defects in expression of genes related
to synaptic vesicle trafficking in frontal cortex of Alzheimer’s disease.
Neurobiol Dis 2003;12:97–109.
24. Cowan WM, Sudhof TC, Stevens CF. Synapses. Baltimore: John Hop-
kins University Press, 2001.
25. Liu X, Passant U, Risberg J, Warkentin S, Brun A. Synapse density
related to cerebral blood flow and symptomatology in frontal lobe
degeneration and Alzheimer’s disease. Dement Geriatr Cogn Disord
26. Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates patholog-
ical effects of microglia on tau phosphorylation and on synaptophysin
synthesis in cortical neurons through a p38-MAPK pathway. J Neuro-
27. Ji D, Lape R, Dani JA. Timing and location of nicotinic activity en-
hances or depresses hippocampal synaptic plasticity. Neuron 2001;31:
28. Callahan LM, Selski DJ, Martzen MR, Cheetham JE, Coleman PD.
Preliminary evidence: decreased GAP-43 message in tangle-bearing
neurons relative to adjacent tangle-free neurons in Alzheimer’s dis-
ease parahippocampal gyrus. Neurobiol Aging 1994;15:381–386.
29. Hatanpaa K, Isaacs KR, Shirao T, Brady DR, Rapoport SI. Loss of
proteins regulating synaptic plasticity in normal aging of the human
brain and in Alzheimer disease. J Neuropathol Exp Neurol 1999;58:
30. West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the
pattern of hippocampal neuronal loss in normal ageing and Alzhei-
mer’s disease. Lancet 1994;344:769–772.
31. Bobinski M, Wegiel J, Tarnawski M, et al. Duration of neurofibrillary
changes in the hippocampal pyramidal neurons. Brain Res 1998;799:
32. Morsch R, Simon W, Coleman PD. Neurons may live for decades with
neurofibrillary tangles. J Neuropathol Exp Neurol 1999;58:188–197.
33. Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton
changes related to the formation of neurofibrillary tangles and neuro-
pil threads. Acta Neuropathol (Berl) 1994;87:554–567.
34. Buell SJ, Coleman PD. Dendritic growth in the aged human brain and
failure of growth in senile dementia. Science 1979;206:854–856.
35. Braak E, Braak H. Alzheimer’s disease: transiently developing den-
dritic changes in pyramidal cells of sector CA1 of the Ammon’s horn.
Acta Neuropathol (Berl) 1997;93:323–325.
36. Cataldo AM, Barnett JL, Berman SA, et al. Gene expression and
cellular content of cathepsin D in Alzheimer’s disease brain: evidence
for early up-regulation of the endosomal–lysosomal system. Neuron
37. Hatanpaa K, Brady DR, Stoll J, Rapoport SI, Chandrasekaran K.
Neuronal activity and early neurofibrillary tangles in Alzheimer’s dis-
ease. Ann Neurol 1996;40:411–420.
38. Callahan LM, Vaules WA, Coleman PD. Quantitative decrease in syn-
aptophysin message expression and increase in cathepsin D message
expression in Alzheimer disease neurons containing neurofibrillary
tangles. J Neuropathol Exp Neurol 1999;58:275–287.
39. Vincent I, Zheng JH, Dickson DW, Kress Y, Davies P. Mitotic phospho-
epitopes precede paired helical filaments in Alzheimer’s disease. Neu-
robiol Aging 1998;19:287–296.
40. Callahan LM, Vaules WA, Coleman PD. Progressive reduction of syn-
aptophysin message in single neurons in Alzheimer disease. J Neuro-
pathol Exp Neurol 2002;61:384–395.
41. Gomez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with
but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol
42. Bertoni-Freddari C, Fattoretti P, Casoli T, Caselli U, Meier-Ruge W.
Deterioration threshold of synaptic morphology in aging and senile
dementia of Alzheimer’s type. Anal Quant Cytol Histol 1996;18:209–
43. Braak H, Braak E. Neuropathological staging of Alzheimer-related
changes. Acta Neuropathol (Berl) 1991;82:239–259.
44. Terry RD. Where in the brain does Alzheimer’s disease begin? Ann
45. Sholl D. Organization of the cerebral cortex. London, Methuen; New
York, Wiley, 1956.
46. Davies CA, Mann DM, Sumpter PQ, Yates PO. A quantitative morpho-
metric analysis of the neuronal and synaptic content of the frontal and
temporal cortex in patients with Alzheimer’s disease. J Neurol Sci
47. Tiraboschi P, Hansen LA, Alford M, Masliah E, Thal LJ, Corey-Bloom
J. The decline in synapses and cholinergic activity is asynchronous in
Alzheimer’s disease. Neurology 2000;55:1278–1283.
48. Brodin L, Low P, Shupliakov O. Sequential steps in clathrin-mediated
synaptic vesicle endocytosis. Curr Opin Neurobiol 2000;10:312–320.
49. Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic
function. Neuron 2003;37:925–937.
50. Lue LF, Kuo YM, Roher AE, et al. Soluble amyloid beta peptide con-
centration as a predictor of synaptic change in Alzheimer’s disease.
Am J Pathol 1999;155:853–862.
51. Mattson MP, Gary DS, Chan SL, Duan W. Perturbed endoplasmic
reticulum function, synaptic apoptosis and the pathogenesis of Alzhei-
mer’s disease. Biochem Soc Symp 2001;67:151–162.
52. Arias C, Montiel T, Quiroz-Baez R, Massieu L. Beta-amyloid neurotox-
icity is exacerbated during glycolysis inhibition and mitochondrial im-
pairment in the rat hippocampus in vivo and in isolated nerve
terminals: implications for Alzheimer’s disease. Exp Neurol 2002;176:
53. Redwine JM, Kosofsky B, Jacobs RE, et al. Dentate gyrus volume is
reduced before onset of plaque formation in PDAPP mice: a magnetic
resonance microscopy and stereologic analysis. Proc Natl Acad Sci
54. Cao X, Sudhof TC. A transcriptionally active complex of APP with
Fe65 and histone acetyltransferase Tip60. Science 2001;293:115–120.
55. Masliah E, Terry R. The role of synaptic proteins in the pathogenesis
of disorders of the central nervous system. Brain Pathol 1993;3:77–85.
October (1 of 2) 2004
56. Davidsson P, Blennow K. Neurochemical dissection of synaptic pathol-
ogy in Alzheimer’s disease. Int Psychogeriatr 1998;10:11–23.
57. Callahan LM, Coleman PD. Neurons bearing neurofibrillary tangles
are responsible for selected synaptic deficits in Alzheimer’s disease.
Neurobiol Aging 1995;16:311–314.
58. Heinonen O, Soininen H, Sorvari H, et al. Loss of synaptophysin-like
immunoreactivity in the hippocampal formation is an early phenome-
non in Alzheimer’s disease. Neuroscience 1995;64:375–384.
59. Yao PJ, Coleman PD. Reduction of O-linked N-acetylglucosamine-
modified assembly protein-3 in Alzheimer’s disease. J Neurosci 1998;
60. Yao PJ, Morsch R, Callahan LM, Coleman PD. Changes in synaptic
expression of clathrin assembly protein AP180 in Alzheimer’s disease
analysed by immunohistochemistry. Neuroscience 1999;94:389–394.
61. Chapman PF, White GL, Jones MW, et al. Impaired synaptic plasticity
and learning in aged amyloid precursor protein transgenic mice. Nat
62. Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Man-
delkow E. Tau domains, phosphorylation, and interactions with micro-
tubules. Neurobiol Aging 1995;16:355–363.
63. Mandelkow EM, Schweers O, Drewes G, et al. Structure, microtubule
interactions, and phosphorylation of tau protein. Ann NY Acad Sci
64. Li Y, Liu L, Kang J, et al. Neuronal–glial interactions mediated by
interleukin-1 enhance neuronal acetylcholinesterase activity and
mRNA expression. J Neurosci 2000;20:149–155.
65. Barger SW, Basile AS. Activation of microglia by secreted amyloid
precursor protein evokes release of glutamate by cystine exchange and
attenuates synaptic function. J Neurochem 2001;76:846–854.
66. Barger SW, Harmon AD. Microglial activation by Alzheimer amyloid
precursor protein and modulation by apolipoprotein E. Nature 1997;
67. Klein WL. ADD. Ls and protofibrils—the missing links? Neurobiol
68. Gong Y, Chang L, Viola KL, et al. Alzheimer’s disease–affected brain:
presence of oligomeric A? ligands (ADDLs) suggest a molecular basis
for reversible memory loss. Proc Natl Acad Sci USA 2003;100:10417–
69. Wang H-W, Pasternak JF, Kuo H, et al. Soluble oligomers of beta
amyloid (1–42) inhibit long-term potentiation but not long-term de-
pression in rat dentate gyrus. Brain Res 2002;924:133–140.
70. Lambert MP, Barlow AK, Chromy BA, et al. Diffusible, nonfibrillar
ligands derived from A? 1–42 are potent central nervous system neu-
rotoxins. Proc Natl Acad Sci USA 1998;95:6448–6453.
71. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in
different age categories. Neurobiol Aging 1997;18:351–357.
72. Mucke L, Masliah E, Yu GQ, et al. High-level neuronal expression of
abeta 1–42 in wild-type human amyloid protein precursor transgenic
mice: synaptotoxicity without plaque formation. J Neurosci 2000;20:
73. Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT,
Nixon RA. Endocytic pathway abnormalities precede amyloid beta
deposition in sporadic Alzheimer’s disease and Down syndrome: differ-
ential effects of APOE genotype and presenilin mutations. Am J
74. Dodart JC, Mathis C, Saura J, Bales KR, Paul SM, Ungerer A. Neuro-
anatomical abnormalities in behaviorally characterized APP(V717F)
transgenic mice. Neurobiol Dis 2000;7:71–85.
75. Weaver CL, Espinoza M, Kress Y, Davies P. Conformational change as
one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol
76. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR,
Markesbery WR. Linguistic ability in early life and cognitive function
and Alzheimer’s disease in late life. Findings from the Nun Study.
77. Raisman G. Neuronal plasticity in the septal nuclei of the adult rat.
Brain Res 1969;14:25–48.
78. Steward O, Cotman C, Lynch G. A quantitative autoradiographic and
electrophysiological study of the reinnervation of the dentate gyrus by
the contralateral entorhinal cortex following ipsilateral entorhinal le-
sions. Brain Res 1976;114:181–200.
79. Cotman C, Nadler J. Reactive synaptogenesis in the hippocampus. In:
Cotman C, ed. Neuronal plasticity. New York: Raven Press, 1978.
80. Hoff SF, Scheff SW, Cotman CW. Lesion-induced synaptogenesis in
the dentate gyrus of aged rats: II. Demonstration of an impaired
degeneration clearing response. J Comp Neurol 1982;205:253–259.
81. Reeves TM, Smith DC. Reinnervation of the dentate gyrus and recov-
ery of alternation behavior following entorhinal cortex lesions. Behav
82. Coleman PD, Flood DG. Neuron numbers and dendritic extent in
normal aging and Alzheimer’s disease. Neurobiol Aging 1987;8:521–
83. Harigaya Y, Shoji M, Shirao T, Hirai S. Disappearance of actin-
binding protein, drebrin, from hippocampal synapses in Alzheimer’s
disease. J Neurosci Res 1996;43:87–92.
84. Mesulam M. Some cholinergic themes related to Alzheimer’s disease:
synaptology of the nucleus basalis, location of m2 receptors, interac-
tions with amyloid metabolism, and perturbations of cortical plastic-
ity. J Physiol 1998;92:293–298.
85. Geddes JW, Monaghan DT, Cotman CW, Lott IT, Kim RC, Chui HC.
Plasticity of hippocampal circuitry in Alzheimer’s disease. Science
86. Scheff S, Price D. Synaptic loss in the temporal lobe in Alzheimer’s
disease. Ann Neurol 1993;33:190–199.
87. Coleman PD, Kazee AM, Lapham L, Eskin T, Rogers K. Reduced
GAP-43 message levels are associated with increased neurofibrillary
tangle density in the frontal association cortex (area 9) in Alzheimer’s
disease. Neurobiol Aging 1992;13:631–639.
88. Masliah E, Mallory M, Hansen L, et al. Patterns of aberrant sprouting
in Alzheimer’s disease. Neuron 1991;6:729–739.
89. Cotman CW, Anderson KJ. Synaptic plasticity and functional stabili-
zation in the hippocampal formation: possible role in Alzheimer’s dis-
ease. Adv Neurol 1988;47:313–335.
90. Scheff SW, DeKosky ST, Price DA. Quantitative assessment of cortical
synaptic density in Alzheimer’s disease. Neurobiol Aging 1990;11:29–37.
91. Bertoni-Freddari C, Fattoretti P, Casoli T, Meier-Ruge W, Ulrich J.
Morphological adaptive response of the synaptic junctional zones in
the human dentate gyrus during aging and Alzheimer’s disease. Brain
92. Bertoni-Freddari C, Fattoretti P, Pieroni M, Meier-Ruge W, Ulrich J.
Enlargement of synaptic size as a compensative reaction in aging and
dementia. Pathol Res Pract 1992;188:612–615.
93. Adams IM. Structural plasticity of synapses in Alzheimer’s disease.
Mol Neurobiol 1991;5:411–419.
94. Domenici L, Berardi N, Carmignoto G, Vantini G, Maffei L. Nerve
growth factor prevents the amblyopic effects of monocular deprivation.
Proc Natl Acad Sci USA 1991;88:8811–8815.
95. Tancredi V, D’Arcangelo G, Mercanti D, Calissano P. Nerve growth
factor inhibits the expression of long-term potentiation in hippocampal
slices. Neuroreport 1993;4:147–150.
96. Castren E, Pitkanen M, Sirvio J, et al. The induction of LTP increases
BDNF and NGF mRNA but decreases NT-3 mRNA in the dentate
gyrus. Neuroreport 1993;4:895–898.
97. Shinsky N, Nishimura M, Zheng J, Phillips H, Gao W. Mice heterozy-
gous for nerve growth factor (NGF) gene depletion show deficit in
synaptic plasticity in the hippocampus. In: Neurotrophic factors: bio-
logical effects IV. South San Francisco, Society for Neuroscience, 1995:
98. Patterson S, Abel T, Ernfors P, Jaenisch R, Kandel E. Deficits in
short-term plasticity and LTP in hippocampal slices from BDNF
knockout mice. In: Neurotrophic factors: expression and regulation.
Cambridge, MA, Society for Neuroscience, 1995:32.
99. McLean Bolton M, Pittman AJ, Lo DC. Brain-derived neurotrophic
factor differentially regulates excitatory and inhibitory synaptic trans-
mission in hippocampal cultures. J Neurosci 2000;20:3221–3232.
100. Drake CT, Milner TA, Patterson SL. Ultrastructural localization of
full-length trkB immunoreactivity in rat hippocampus suggests multi-
ple roles in modulating activity-dependent synaptic plasticity. J Neu-
101. Lu B. BDNF and activity-dependent synaptic modulation. Learn Mem-
102. Goggi J, Pullar IA, Carney SL, Bradford HF. Signalling pathways
involved in the short-term potentiation of dopamine release by BDNF.
Brain Res 2003;968:156–161.
103. Broad KD, Mimmack ML, Keverne EB, Kendrick KM. Increased
BDNF and trk-B mRNA expression in cortical and limbic regions
following formation of a social recognition memory. Eur J Neurosci
104. Castren M, Lampinen KE, Miettinen R, et al. BDNF regulates the
expression of fragile X mental retardation protein mRNA in the hip-
pocampus. Neurobiol Dis 2002;11:221–229.
105. Zhang X, Poo MM. Localized synaptic potentiation by BDNF requires
local protein synthesis in the developing axon. Neuron 2002;36:675–
106. Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte
M. Mechanism of TrkB-mediated hippocampal long-term potentiation.
107. Tolwani RJ, Buckmaster PS, Varma S, et al. BDNF overexpression
increases dendrite complexity in hippocampal dentate gyrus. Neuro-
108. Alonso M, Vianna MR, Depino AM, et al. BDNF-triggered events in
the rat hippocampus are required for both short- and long-term mem-
ory formation. Hippocampus 2002;12:551–560.
109. Ishibashi H, Hihara S, Takahashi M, Heike T, Yokota T, Iriki A.
Tool-use learning induces BDNF expression in a selective portion of
monkey anterior parietal cortex. Brain Res Mol Brain Res 2002;102:
110. Messaoudi E, Ying SW, Kanhema T, Croll SD, Bramham CR. Brain-
derived neurotrophic factor triggers transcription-dependent, late
phase long-term potentiation in vivo. J Neurosci 2002;22:7453–7461.
111. Yamada MK, Nakanishi K, Ohba S, et al. Brain-derived neurotrophic
factor promotes the maturation of GABAergic mechanisms in cultured
hippocampal neurons. J Neurosci 2002;22:7580–7585.
October (1 of 2) 2004
112. Berchtold NC, Kesslak JP, Cotman CW. Hippocampal brain-derived Download full-text
neurotrophic factor gene regulation by exercise and the medial sep-
tum. J Neurosci Res 2002;68:511–521.
113. Roceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA. Early
maternal deprivation reduces the expression of BDNF and NMDA recep-
tor subunits in rat hippocampus. Mol Psychiatry 2002;7:609–616.
114. Ying SW, Futter M, Rosenblum K, et al. Brain-derived neurotrophic
factor induces long-term potentiation in intact adult hippocampus:
requirement for ERK activation coupled to CREB and upregulation of
Arc synthesis. J Neurosci 2002;22:1532–1540.
115. Carter AR, Chen C, Schwartz PM, Segal RA. Brain-derived neurotro-
phic factor modulates cerebellar plasticity and synaptic ultrastructure.
J Neurosci 2002;22:1316–1327.
116. Yamada K, Nabeshima T. Brain-derived neurotrophic factor/TrkB sig-
naling in memory processes. J Pharmacol Sci 2003;91:267–270.
117. Yamada K, Mizuno M, Nabeshima T. Role for brain-derived neurotro-
phic factor in learning and memory. Life Sci 2002;70:735–744.
118. Frost D. BDNF/trkB signaling in the developmental sculpting of vi-
sual connections. Prog Brain Res 2001;134:35–49.
119. Li YX, Tokuyama W, Okuno H, Miyashita Y, Hashimoto T. Differential
induction of brain-derived neurotrophic factor mRNA in rat inferior olive
subregions following unilateral labyrinthectomy. Neuroscience 2001;106:
120. Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, Lu B. Protein
synthesis-dependent and -independent regulation of hippocampal syn-
apses by brain-derived neurotrophic factor. J Biol Chem 2001;276:
121. Vollmayr B, Faust H, Lewicka S, Henn FA. Brain-derived-
neurotrophic-factor (BDNF) stress response in rats bred for learned
helplessness. Mol Psychiatry 2001;6:471–474.
122. Gooney M, Lynch MA. Long-term potentiation in the dentate gyrus of
the rat hippocampus is accompanied by brain-derived neurotrophic
factor-induced activation of TrkB. J Neurochem 2001;77:1198–1207.
123. Hepp R, Dupont JL, Aunis D, Langley K, Grant NJ. NGF enhances
depolarization effects on SNAP-25 expression: induction of SNAP-25b
isoform. Neuroreport 2001;12:673–677.
124. Kohara K, Kitamura A, Morishima M, Tsumoto T. Activity-dependent
transfer of brain-derived neurotrophic factor to postsynaptic neurons.
125. Canossa M, Gartner A, Campana G, Inagaki N, Thoenen H. Regulated
secretion of neurotrophins by metabotropic glutamate group I
(mGluRI) and Trk receptor activation is mediated via phospholipase C
signalling pathways. Embo J 2001;20:1640–1650.
126. Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymor-
phism affects activity-dependent secretion of BDNF and human mem-
ory and hippocampal function. Cell 2003;112:257–269.
127. Blochl A, Thoenen H. Localization of cellular storage compartments
and sites of constitutive and activity-dependent release of nerve
growth factor (NGF) in primary cultures of hippocampal neurons. Mol
Cell Neurosci 1996;7:173–190.
128. Blochl A, Thoenen H. Characterization of nerve growth factor (NGF)
release from hippocampal neurons: evidence for a constitutive and an
unconventional sodium-dependent regulated pathway. Eur J Neurosci
129. Lee R, Kermani P, Teng K, Hempstead B. Regulation of cell survival
by secreted proneurotrophins. Science 2001;294:1945–1948.
130. Brooks AI, Muhkerjee B, Panahian N, Cory-Slechta D, Federoff
HJ. Nerve growth factor somatic mosaicism produced by herpes virus-
directed expression of cre recombinase. Nat Biotechnol 1997;15:57–62.
131. Brooks AI, Cory-Slechta DA, Federoff HJ. Gene–experience interac-
tion alters the cholinergic septohippocampal pathway of mice. Proc
Natl Acad Sci USA 2000;97:13378–13383.
132. Brooks AI, Halterman MW, Federoff HJ. Focal hippocampal gain of
NGF function elicits specific septal cholinergic reorganization. Neuro-
October (1 of 2) 2004