JOURNAL OF NEUROCHEMISTRY | 2012 | 120 (Suppl. 1) | 140–148
Center for Neural Science, New York University, New York, New York, USA
Abstract
Mounting evidence suggests that amyloid beta-induced
impairments in synaptic plasticity that is accompanied by
cognitive decline and dementia represent key pathogenic
steps of Alzheimer’s disease. In this study, we review recent
advances in the study of the molecular and cellular mecha-
nisms underlying Alzheimer’s disease-associated synaptic
In April 1906, Auguste Deter, the first described Alzheimer
patient, died, five years after she first was examined by
Dr Alois Alzheimer. With state of the art staining techniques in
use at that time, Dr Alzheimer and his colleagues were able
to examine the brain pathology of Mrs Deter and identified
the now well-known, characteristic ‘plaques’. However, what
these plaques were composed of remained a mystery until
eight decades later when a sticky peptide called amyloid beta
(Ab) was purified and sequenced with modern biochemical
methods (Glenner and Wong 1984; Masters et al. 1985). The
discovery of Ab launched a new era of research on
Alzheimer’s disease (AD) and a new framework to explain
AD pathogenesis. AD is the most common form of dementia
and gradually gets worse over time, with aging being the
highest risk factor (Querfurth and LaFerla 2010). In this
review, we focus our discussion on the role of Ab in
impairments in synaptic plasticity and memory function. Our
objective is to discuss recent advances in the study of the
molecular and cellular mechanisms underlying AD-associ-
ated synaptic dysfunction and memory impairment, and how
these mechanisms could provide novel avenues for thera-
peutic intervention in this devastating disease of memory.
Ab-induced memory impairment
It has been revealed that Ab is derived from amyloid
precursor protein (APP) via abnormal sequential cleavage by
b- and c-secretases (Kang et al. 1987; Esch et al. 1990;
Selkoe 1998). Strong support for the pathogenic role of Ab
in AD first arose with breakthrough genetic findings in
Ó 2011 The Authors
140 Journal of Neurochemistry Ó 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120 (Suppl. 1), 140–148
doi: 10.1111/j.1471-4159.2011.07506.
dysfunction and memory deficits, and how these mechanisms
could provide novel avenues for therapeutic intervention to
treat this devastating neurodegenerative disease.
Keywords: amyloid b, glycogen synthase kinase-3, long-term
potentiation, mammalian target of rapamycin, NMDA recep-
tors, reactive oxygen species.
J. Neurochem. (2012) 120 (Suppl. 1), 140–148.
familial AD cases, of which a significant portion carry either
APP or presenilin (PS, part of the c-secretase complex)
mutations, resulting in unusually high Ab levels and early
onset of dementia, which in most regards is identical to
sporadic AD (Selkoe 1998; Chapman et al. 2001). Further-
more, most, if not all, transgenic mice that have been utilized
to model AD and to evaluate potential therapeutic interven-
tions have included human APP and/or PS mutations because
these mice replicate AD-like amyloid deposition and age-
related, progressive memory impairment (Ashe 2001; Janus
and Westaway 2001; Zahs and Ashe 2010).
Another piece of compelling evidence of Ab being a
causative factor in AD comes from studies in which synthetic
Ab was injected directly into various brain areas of animals,
primarily the hippocampus. In these studies, microinjection
of the Ab peptide impaired working memory in a manner
consistent with this type of memory deficit in AD patients
(McDonald et al. 1994; Cleary et al. 1995; Stéphan et al.
2001). Given that Ab by nature is a ‘sticky’ peptide that
tends to aggregate, an interesting question has arisen as to
Received July 1, 2011; revised manuscript received September 8, 2011;
accepted September 20, 2011.
Address correspondence and reprint requests to Eric Klann, PhD,
Center for Neural Science, New York University, 4 Washington Place,
Room 809, New York, NY 10003, USA. E-mail: eklann@cns.nyu.edu
Abbreviations used: AD, Alzheimer’s disease; APP, amyloid precur-
sor protein; GSK3, glycogen synthase kinase-3; LFS, low-frequency
stimulation; LTD, long-term depression; LTP, long-term potentiation;
mTOR, mammalian target of rapamycin; NMDAR, NMDA receptor; PS,
presenilin; ROS, reactive oxygen species; SOD, superoxide dismutase.
 Ab-induced synaptic and memory deficits in AD | 141

what assembled forms of Ab are actually responsible for the

observed memory disruption in AD. A series of studies
utilizing synthetic, natural, and human AD-derived Ab have
indicated that soluble Ab oligomers, with dimers being the
smallest species, are both necessary and sufficient to disrupt
normal learning and memory function (Cleary et al. 2005;
Lesné et al. 2006; Shankar et al. 2008).

Ab abrogates synaptic plasticity

Persistent change in neuronal circuits, or synaptic plasticity,
is widely thought to be required for learning and memory.
One well-known and intensely studied form of synaptic
plasticity at hippocampal synapses is long-term potentiation
(LTP), broadly defined as an activity-dependent increase in
synaptic strength, which is measured by the slope (and/or the
amplitude) of the excitatory post-synaptic potential in a
neuron after either a brief burst of stimulation delivered to
pre-synaptic afferents or following various pharmacological
treatments. Ever since it was described more than 40 years
ago (Bliss and Lomo 1973), LTP has remained the leading
cellular and synaptic model for learning and memory (Bliss
and Collingridge 1993; Malenka and Nicoll 1999; Kandel
2001; Malenka 2003). A plethora of studies have been
conducted to examine the effects of Ab on LTP in vitro and
in vivo. In most cases, LTP can be blocked by either direct
exogenous Ab application (at a concentration of 100 nM or
higher for synthetic Ab) (Fig. 1b), or in AD transgenic
mouse models in which an abnormally high levels of Ab are
present (Rowan et al. 2005). It is interesting to note that
multiple lines of evidence suggest that there is an early, pre-
plaque phase when learning and memory deficits are not
detected in AD transgenic mice, but LTP is already impaired
(Oddo et al. 2003; Jacobsen et al. 2006; Ma et al. 2010)
(Fig. 1c). In addition to the possibility that the behavioral
paradigms being used currently are not sufficiently sensitive
to detect small, early changes in memory function, these Fig. 1 Ab impairs hippocampal long-term potentiation. (a) Schaffer
observations are in line with the hypothesis that soluble Ab collateral efferents are stimulated to elicit a field excitatory post-syn-
aptic potential (fEPSP) at synapses in the dendritic layer of area CA1
oligomers, but not plaque cores, in AD are synaptotoxic
in acute hipocampal slices. (b) Application of exogenous synthetic
(Haass and Selkoe 2007; Querfurth and LaFerla 2010).
Ab1-42 (500 nM) results in the blockade of long-term potentiation
Interestingly, in clinical studies a group of patients has been
(LTP). (c) Hippocampal LTP is impaired in slices from the Tg2576
described with a very subtle memory syndrome, but they do transgenic mouse model of Alzheimer’s disease at 3–4 months of age,
not display dementia. These patients, who otherwise have which is before the onset of memory impairments and the formation of
normal cognition, are diagnosed as having minimal (or mild) amyloid plaques. Adapted from Ma et al. (2010).
cognitive impairment, often considered the harbinger of AD
(Selkoe 2004; Querfurth and LaFerla 2010). Thus, these
clinical observations are consistent with the basic experi- Singer 1993; Stanton 1996; Malenka and Bear 2004). It was
mental findings that have demonstrated that hippocampal reported that LTD in vivo induced by low-frequency
LTP impairments appear earlier than behavioral deficits in stimulation (LFS) can be facilitated by injection of different
AD transgenic mice. forms of synthetic Ab (Kim et al. 2001; Cheng et al. 2009).
Compared with LTP, much fewer studies have been Additional studies on LTD in vitro have confirmed that LFS-
conducted to examine the effects of Ab on long-term induced LTD is enhanced by Ab from various sources,
depression (LTD), another form of synaptic plasticity, which including synthetic, cell culture, and human AD brains
is a persistent decrease in synaptic efficacy (Artola and extracts (Shankar et al. 2008; Li et al. 2009). It should be

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Journal of Neurochemistry Ó 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120 (Suppl. 1), 140–148
142 | T. Ma and E. Klann

noted that it also has been reported that LTD induced by

stronger LFS protocol is not altered by Ab (Wang et al.
2002; Raymond et al. 2003).
Although numerous reports indicate that Ab causes
impaired synaptic plasticity, there are paradoxical lines of
evidence from in vitro and in vivo studies that have shown
that increased synaptic activity per se induces Ab secretion
(Kamenetz et al. 2003; Cirrito et al. 2005, 2008). Based on
these reports it has been speculated that though excessive
production of Ab is synaptotoxic, at lower concentrations Ab
may actually serve as a physiological molecule that regulates
normal synaptic plasticity and memory. Indeed, recent
studies indicate not only that endogenous Ab is indispens-
able for normal learning and memory, but also that Ab at
very low concentrations (picomolar) enhances hippocampal
LTP and memory formation (Puzzo et al. 2008; Garcia-Osta
and Alberini 2009).
Another interesting idea has been proposed to address the
‘Ab/synaptic activity paradox’ based on the theory of
intraneuronal Ab. Classically viewed as only being located
extracellularly, mounting evidence from AD transgenic mice
and human patients has pointed to the presence of Ab
intraneuronally that may be involved in disease progression
(Gouras et al. 2005; LaFerla et al. 2007). Based on findings
that intraneuronal Ab is reduced by synaptic activation,
whereas it is increased by synaptic inhibition, it has been
proposed that the pool of intracellular and extracellular Ab is
linked dynamically, and that it is the accumulation of
intraneuronal Ab that initiates its synaptotoxic effects
(Tampellini et al. 2009, 2010; Gouras et al. 2010).
Deciphering the cellular mechanisms of Ab-
induced synaptic dysfuction
Developing a mechanistic understanding of the ability of Ab
to interfere with synaptic plasticity and memory could yield
important insights into the pathophysiology of AD. During the
past ten years, many groups have carried out elegant studies
exploring the potential molecular and cellular signaling
mechanisms underlying the synaptotoxic effects of Ab. In
the following sections, we will mainly discuss advancements
in studying the role of NMDA receptors (NMDARs),
mitochondrial reactive oxygen species (ROS), glycogen
synthase kinase-3 (GSK3), and the mammalian target of
rapamycin (mTOR) signaling pathways in mediating the toxic
effects of Ab on synaptic function. Remarkably, even though
these mechanisms are often explored separately in AD
research, it is possible that they are interconnected based on
current understanding of cell signaling pathways (Fig. 2).
NMDA receptors
NMDA receptors are glutamate-gated, heteromeric ion
channels that are highly permeable to Ca2+. The number
Fig. 2 Signaling pathways that have been demonstrated to contribute
to Ab-induced impairments in hippocampal long-term potentiation.
and subunit composition of synaptic NMDARs constantly
change during development and in response to neuronal
activity and sensory experience. Indeed, activity-dependent,
bidirectional regulation of delivery and targeting of
NMDARs to synapses is known to play a pivotal role in
synaptic plasticity (LTP and LTD), and in learning and
memory (Lau and Zukin 2007; Lau et al. 2009; Rebola et al.
2010; Gladding and Raymond 2011). It has been argued that
either too little or too much NMDAR activity is harmful to
neurons (Hardingham and Bading 2003). Ab has been shown
to interfere with normal NMDAR trafficking by triggering
receptor internalization, thus reducing the number of surface
NMDARs (Snyder et al. 2005). Later, it was demonstrated
that Ab oligomers reduce NMDAR-mediated Ca2+ influx
into active dendritic spines (Shankar et al. 2007). Further-
more, a recent study suggests that depletion of the receptor
tyrosine kinase EphB2 mediates Ab-induced NMDAR
blockade (Cissé et al. 2011).
Though most studies on NMDARs have focused on
synaptic NMDARs that are largely located at the post-
synaptic density, NMDARs also exist outside synapses, and
these extrasynaptic NMDARs likely have distinct roles in
signaling transduction and gene regulation (Hardingham
et al. 2002; Lau and Zukin 2007). Recently, it has been
reported that over-activation of extrasynaptic NR2B-contain-
ing NMDARs may be involved in Ab-induced LTD
enhancement and LTP inhibition (Li et al. 2009, 2011).
Interestingly, it also was shown that memantine, an NMDAR
antagonist and FDA-approved drug for AD treatment,
preferentially blocks extrasynaptic rather than synaptic
NMDAR-mediated currents (Xia et al. 2010), providing
further evidence for a role of extrasynaptic NMDARs in the
pathophysiology of AD.

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Mitochondrial ROS
The role of ROS in synaptic plasticity and memory has been
described as a ‘double-edged sword’ (Massaad and Klann
2011). On one hand, ROS have a physiological role, in that
their production is necessary to maintain normal synaptic
plasticity, probably via activation of certain key signaling
molecules such as protein kinase C and mitogen-activated
protein kinases (Bindokas et al. 1996; Klann 1998; Klann
et al. 1998; Knapp and Klann 2002; Kishida et al. 2005;
Huddleston et al. 2008). On the other hand, ROS have been
linked to synaptic pathology associated with aging and
neurodegenerative diseases, including AD (Balaban et al.
2005; Lin and Beal 2006). Indeed, recent investigations on
brains of pre-clinical AD patients have provided evidence
that oxidative stress is one of the earliest changes in AD
pathogenesis (Zhu et al. 2007; Smith et al. 2010). Not
surprisingly, various types of ROS-mediated oxidative stress
are used consistently as biomarkers of AD brain pathology
(Praticò 2008). It is likely that in pathological situations,
unusually high levels of ROS are produced constantly,
overwhelming the ability of the endogenous antioxidants,
including superoxide dismutase (SOD) and vitamins E and C
to remove them, which then results in impairments in
synaptic function (Fig. 3). For example, AD mutant mice
with decreased mitochondrial SOD (SOD-2) expression
exhibit elevated levels of brain Ab and accelerated cognitive
dysfunction (Li et al. 2004; Esposito et al. 2006). Con-
Fig. 3 Abnormal accumulation of Ab in Alzheimer’s disease induces
overproduction of reactive oxygen species (ROS), such as superoxide
anion, hydrogen peroxide, and hydroxyl radicals, which overwhelms
the ability of endogenous antioxidant systems (superoxide dismutate,
vitamins C and E, etc.) to effectively remove ROS. Consequently, the
role of ROS as physiological molecules in mediating normal synaptic
plasticity and memory becomes subordinate to their detrimental ef-
fects as oxidative stressors, resulting in impairments of synaptic
plasticity and memory.
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Ab-induced synaptic and memory deficits in AD | 143
versely, it has been shown that over-expression of SOD-2 in
two different AD mouse models is capable of reducing brain
Ab deposition and preventing memory deficits (Dumont
et al. 2009; Massaad et al. 2009). More recently, it was
demonstrated using both pharmacological and genetic
approaches that AD-associated synaptic plasticity impair-
ments can be prevented and reversed by targeting ROS
derived from mitochondria, but not NADPH oxidase (Ma
et al. 2011). An interesting implication that arises from these
and other studies is that ROS play different roles in synaptic
plasticity, depending either on their subcellular localization
or on the age of the animals being studied (Kamsler and
Segal 2003; Hu et al. 2006, 2007). Such complexity of ROS
function in the nervous system and their diverse effects on
synaptic function may also help interpret the observation that
current clinical trials with antioxidants such as vitamin E
resulted in either a marginally positive effect or no effect on
the cognitive function of AD patients (Praticò 2008).
Glycogen synthase kinase-3
Two isoforms of GSK3 exist, GSK3a and GSK3b. The two
GSK isoforms are encoded by different genes, but are
virtually identical in their catalytic regions (Woodgett 1990;
Jope and Johnson 2004). For reasons that are not obvious,
the majority of studies have focused on GSK3b, and the
tissue-specific distribution, cellular localization, and func-
tions of the two isoforms are controversial (Woodgett 1990;
Hoeflich et al. 2000; Asuni et al. 2006; Doble et al. 2007;
MacAulay et al. 2007; Force and Woodgett 2009). GSK3 is
unusual in that its constituitive activity is high and reduced
with phosphorylation (Ser 9 in GSK3b and Ser 21 in
GSK3a) by upstream kinases including Akt and Wnt (Hur
and Zhou 2010). Initially identified as a regulator of
glycogen metabolism (Embi et al. 1980), GSK3 is now
widely recognized as a critical component involved into
many cellular processes, and GSK3 dysfunction has been
implicated in major diseases (Frame and Cohen 2001; Jope
and Johnson 2004). Dysregulation of GSK3 activity has been
observed in both sporadic and familial AD cases. Many lines
of evidence point to a role of GSK3 in the development of
both classical neuropathological features of AD, including
amyloid plaques and neurofibrillary tangles that are mainly
composed of hyperphosphorylated tau (Jope and Johnson
2004; Hooper et al. 2008). Below, we will limit our
discussion on the interaction between GSK3 and Ab.
Increasing evidence suggests that the relationship between
GSK3 and Ab is probably bidirectional. For example, high
GSK3 activity may interfere with normal APP processing via
modulation of the function of secretases, leading to Ab
accumulation (Sun et al. 2002; Phiel et al. 2003; Hooper
et al. 2008). Suppression of GSK3 activity by either
pharmacological inhibitors or genetic manipulations results
in abolishment of Ab production and reducing plaque
144 | T. Ma and E. Klann
pathology in the brains of AD transgenic mice (Phiel et al.
2003; Su et al. 2004). Interestingly, in one study the effects
on APP cleavage and Ab production were specifically
attributed to GSK3a and not GSK3b (Phiel et al. 2003). In
contrast, Ab can activate GSK3 through dephosporylation,
which is linked to down-regulation of the PI3K/Akt signaling
pathway (Magrané et al. 2005; Peineau et al. 2008; Terwel
et al. 2008; Lee et al. 2009; Jo et al. 2011).
GSK3 also has been proposed to play an important role in
synaptic plasticity (Peineau et al. 2007, 2008) and evidence
is accumulating to suggest the therapeutic potential of GSK3
inhibition for AD-related synaptic dysfunction. For example,
it was reported that hippocampal LTP impairments in an AD
transgenic mouse could be rescued by two structurally
distinct GSK3 antagonists (Ma et al. 2010). Moreover, it was
reported recently that Ab-induced LTP failure can be
prevented by pre-treatment of brain slices with a specific
GSK3 inhibitor (Jo et al. 2011). Compared with the abun-
dance of evidence from in vitro studies linking GSK3 activity
to the pathogenesis of AD, much less is known about the role
of GSK3 in AD in vivo. A recent study examined the in vivo
effects of lithium, an inhibitor of GSK3, on AD transgenic
mice and observed that although lithium was able to improve
cognitive function at early stages, such ability was lost in
aged AD transgenic mice (Fiorentini et al. 2010). Other new
and more specific small molecule inhibitors of GSK3 may
have better potential than lithium as an AD therapy, though
more investigations are needed to confirm this possibility
(Balaraman et al. 2006).
Mammalian target of rapamycin
Mammalian target of rapamycin is an evolutionarily con-
served serine/threonine protein kinase that plays an essential
role in the control of mRNA translation and cell growth (Hay
and Sonenberg 2004; Averous and Proud 2006; Yang and
Guan 2007). Interestingly, mTOR assembles into two distinct
complexes, mTORC1 and mTORC2, distinguished by dif-
ferent binding proteins associated with mTOR and sensitivity
to rapamycin (Bhaskar and Hay 2007; Huang and Manning
2009; Hoeffer and Klann 2010). To our knowledge, all
studies conducted thus far on AD have examined only
mTORC1 (referred as mTOR hereafter for the purpose of
simplicity). Numerous reports have firmly established a
pivotal role of mTOR in CNS function, including studies
that have shown that the activation of mTOR and the
subsequent stimulation of translation initiation to boost
translational capacity is crucial for long-lasting synaptic
plasticity and the consolidation of long-term memory (Richter
and Klann 2009; Hoeffer and Klann 2010). Moreover,
evidence linking mTOR to synaptic plasticity and long-term
memory has been derived from studies using either pharma-
cological agents or genetically-modified mice, which have
demonstrated that disruption of mTOR signaling results in
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Journal of Neurochemistry Ó 2011 International Society for Neurochemistry, J. Neurochem. (2012) 120 (Suppl. 1), 140–148
impairment of learning and memory function (Banko et al.
2005, 2007; Parsons et al. 2006; Antion et al. 2008; Blundell
et al. 2008; Gafford et al. 2011; Hoeffer et al. 2011; Stoica
et al. 2011).
There is recent evidence suggesting a link between mTOR
and AD, although the exact role that mTOR plays in AD is
controversial. The first controversy arises from a basic
question: how is mTOR regulated (or dysregulated) in AD?
Decreased mTOR signaling has been reported in the brains of
an APP-PS1 AD transgenic mouse model (Lafay-Chebassier
et al. 2005), which is consistent with subsequent findings
that rapamycin, a specific inhibitor of mTORC1, exacerbates
neurotoxicity of Ab (Lafay-Chebassier et al. 2006). In
contrast, up-regulation of mTOR signaling has been reported
in postmortem human AD brains, particularly in tangle-
bearing neurons (An et al. 2003). This finding is in
agreement with a recent report showing that mTOR signaling
is enhanced in the triple-transgenic mouse model of AD,
which in addition to APP and PS mutations, also contains a
tau mutation (Caccamo et al. 2010). However, a more recent
study with Tg2576 AD model mice revealed that mTOR
signaling is down-regulated at early ages, but not in the aged
transgenic mice (Ma et al. 2010). Yet, another study of the
PDAPP [also known as hAPP(J20)] AD transgenic mouse
model reported no alteration in mTOR signaling (Spilman
et al. 2010). One possibility for the discrepancies among
these studies is that each of them utilized a different AD
mouse model. Therefore, it is possible that the regulation of
mTOR by a mutation in PS and/or tau alters the response of
mTOR to excess Ab. This possibility seems likely because
mTOR is well known to integrate multiple signaling
pathways in response to diverse stimuli, including stress
and inflammation (Reiling and Sabatini 2006; Hoeffer and
Klann 2010).
Given the diversity of findings on mTOR dysregulation in
AD, it should not be surprising that there is disagreement
concerning whether mTOR should be targeted therapeuti-
cally as a treatment for AD. This issue is complicated further
because of critical studies on the association between the
mammalian aging process and the mTOR pathway that have
shown that either feeding mice rapamycin or genetically
deleting ribosomal S6 protein kinase 1 (S6K1), a down-
stream effector of mTOR, results in increased life span
(Harrison et al. 2009; Selman et al. 2009). However,
whether either hippocampal synaptic plasticity or hippocam-
pus-dependent memory function was impacted in the animals
was not addressed in these studies. Given the fact that aging
is a well-established risk factor for AD, two groups recently
conducted studies where AD transgenic mice were fed
rapamycin to inhibit mTOR signaling and found that
cognitive deficits could be rescued (Caccamo et al. 2010;
Spilman et al. 2010). In contrast, around the same time it was
reported that Ab-induced impairments in synaptic plasticity
could be reversed by up-regulating mTOR signaling via

either pharmacological methods or a genetic manipulation
(Ma et al. 2010).
How does one reconcile these seemingly conflicting
findings with respect to mTOR, rapamycin, and AD? First,
it should be noted that the mTOR pathway was manipulated
in quite different ways (e.g. chronic vs. acute), and focused
on different aspects of mTOR function (e.g. autophagy-
related Ab changes vs. as a signaling molecule in synaptic
plasticity). Moreover, a similar paradox exists in AD research
with respect to the insulin-PI3K-Akt pathway, which have
been well recognized as upstream regulators of mTOR. Ab
was shown to impair insulin-PI3K-Akt signaling (Magrané
et al. 2005; Townsend et al. 2007; De Felice et al. 2009; Lee
et al. 2009) and insulin treatment was reported to improve
cognitive function in patients with early AD (Reger et al.
2008). In contrast, AD transgenic mice with reduced insulin
signaling are protected against cognitive decline (Cohen
et al. 2009). In summary, there is still significant disagree-
ment regarding the actual in vitro and in vivo role played by
mTOR in AD, and for this reason further investigation is
warranted before rapamycin should be considered as a
treatment for individuals with AD.
Concluding remarks
With an aging population that continues to grow rapidly, the
number of people afflicted with AD has been escalating
considerably. Thus, AD has been proposed as the new
epidemic of the twenty-first century (Dyer et al. 2006).
Given that there is still no available effective treatment for
AD, it is both necessary and urgent that neuroscientists
develop novel therapeutics. A multitude of studies in the past
decade have illuminated AD as a disorder of synaptic
dysfunction due to the synaptotoxic effects of Ab. We look
forward to the translation of the dysregulated moleclular
signaling pathways we have discussed in this review and an
effective treatment for Alzheimer’s disease in the future.
Acknowledgements
This work was supported by National Institutes of Health grants
NS034007 and NS047834, and Alzheimer’s Association Investiga-
tor. This review is dedicated to the memory of Dr. Mark A. Smith, a
great colleague and a better friend.
Conflict of interests
The authors declare no conflict of interests.
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