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Keywords:

  • amyloid β;
  • glycogen synthase kinase-3;
  • long-term potentiation;
  • mammalian target of rapamycin;
  • NMDA receptors;
  • reactive oxygen species

Abstract

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

J. Neurochem. (2012) 120 (Suppl. 1), 140–148.

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 mechanisms underlying Alzheimer’s disease-associated synaptic dysfunction and memory deficits, and how these mechanisms could provide novel avenues for therapeutic intervention to treat this devastating neurodegenerative disease.

Abbreviations used
AD

Alzheimer’s disease

APP

amyloid precursor 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

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 (Aβ) was purified and sequenced with modern biochemical methods (Glenner and Wong 1984; Masters et al. 1985). The discovery of Aβ 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 Aβ 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-associated synaptic dysfunction and memory impairment, and how these mechanisms could provide novel avenues for therapeutic intervention in this devastating disease of memory.

Aβ-induced memory impairment

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

It has been revealed that Aβ is derived from amyloid precursor protein (APP) via abnormal sequential cleavage by β- and γ-secretases (Kang et al. 1987; Esch et al. 1990; Selkoe 1998). Strong support for the pathogenic role of Aβ in AD first arose with breakthrough genetic findings in familial AD cases, of which a significant portion carry either APP or presenilin (PS, part of the γ-secretase complex) mutations, resulting in unusually high Aβ levels and early onset of dementia, which in most regards is identical to sporadic AD (Selkoe 1998; Chapman et al. 2001). Furthermore, most, if not all, transgenic mice that have been utilized to model AD and to evaluate potential therapeutic interventions 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 Aβ being a causative factor in AD comes from studies in which synthetic Aβ was injected directly into various brain areas of animals, primarily the hippocampus. In these studies, microinjection of the Aβ 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 Aβ by nature is a ‘sticky’ peptide that tends to aggregate, an interesting question has arisen as to what assembled forms of Aβ are actually responsible for the observed memory disruption in AD. A series of studies utilizing synthetic, natural, and human AD-derived Aβ have indicated that soluble Aβ oligomers, with dimers being the smallest species, are both necessary and sufficient to disrupt normal learning and memory function (Cleary et al. 2005; Lesnéet al. 2006; Shankar et al. 2008).

Aβ abrogates synaptic plasticity

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

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 Aβ on LTP in vitro and in vivo. In most cases, LTP can be blocked by either direct exogenous Aβ application (at a concentration of 100 nM or higher for synthetic Aβ) (Fig. 1b), or in AD transgenic mouse models in which an abnormally high levels of Aβ 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 observations are in line with the hypothesis that soluble Aβ oligomers, but not plaque cores, in AD are synaptotoxic (Haass and Selkoe 2007; Querfurth and LaFerla 2010). Interestingly, in clinical studies a group of patients has been described with a very subtle memory syndrome, but they do not display dementia. These patients, who otherwise have normal cognition, are diagnosed as having minimal (or mild) cognitive impairment, often considered the harbinger of AD (Selkoe 2004; Querfurth and LaFerla 2010). Thus, these clinical observations are consistent with the basic experimental findings that have demonstrated that hippocampal LTP impairments appear earlier than behavioral deficits in AD transgenic mice.

image

Figure 1.  Aβ impairs hippocampal long-term potentiation. (a) Schaffer collateral efferents are stimulated to elicit a field excitatory post-synaptic potential (fEPSP) at synapses in the dendritic layer of area CA1 in acute hipocampal slices. (b) Application of exogenous synthetic Aβ1-42 (500 nM) results in the blockade of long-term potentiation (LTP). (c) Hippocampal LTP is impaired in slices from the Tg2576 transgenic mouse model of Alzheimer’s disease at 3–4 months of age, which is before the onset of memory impairments and the formation of amyloid plaques. Adapted from Ma et al. (2010).

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Compared with LTP, much fewer studies have been conducted to examine the effects of Aβ on long-term depression (LTD), another form of synaptic plasticity, which is a persistent decrease in synaptic efficacy (Artola and Singer 1993; Stanton 1996; Malenka and Bear 2004). It was reported that LTD in vivo induced by low-frequency stimulation (LFS) can be facilitated by injection of different forms of synthetic Aβ (Kim et al. 2001; Cheng et al. 2009). Additional studies on LTD in vitro have confirmed that LFS-induced LTD is enhanced by Aβ from various sources, including synthetic, cell culture, and human AD brains extracts (Shankar et al. 2008; Li et al. 2009). It should be noted that it also has been reported that LTD induced by stronger LFS protocol is not altered by Aβ (Wang et al. 2002; Raymond et al. 2003).

Although numerous reports indicate that Aβ 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 Aβ secretion (Kamenetz et al. 2003; Cirrito et al. 2005, 2008). Based on these reports it has been speculated that though excessive production of Aβ is synaptotoxic, at lower concentrations Aβ may actually serve as a physiological molecule that regulates normal synaptic plasticity and memory. Indeed, recent studies indicate not only that endogenous Aβ is indispensable for normal learning and memory, but also that Aβ 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 ‘Aβ/synaptic activity paradox’ based on the theory of intraneuronal Aβ. Classically viewed as only being located extracellularly, mounting evidence from AD transgenic mice and human patients has pointed to the presence of Aβ intraneuronally that may be involved in disease progression (Gouras et al. 2005; LaFerla et al. 2007). Based on findings that intraneuronal Aβ is reduced by synaptic activation, whereas it is increased by synaptic inhibition, it has been proposed that the pool of intracellular and extracellular Aβ is linked dynamically, and that it is the accumulation of intraneuronal Aβ that initiates its synaptotoxic effects (Tampellini et al. 2009, 2010; Gouras et al. 2010).

Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

Developing a mechanistic understanding of the ability of Aβ 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 Aβ. 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 Aβ 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).

image

Figure 2.  Signaling pathways that have been demonstrated to contribute to Aβ-induced impairments in hippocampal long-term potentiation.

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NMDA receptors

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

NMDA receptors are glutamate-gated, heteromeric ion channels that are highly permeable to Ca2+. The number 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). Aβ 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 Aβ oligomers reduce NMDAR-mediated Ca2+ influx into active dendritic spines (Shankar et al. 2007). Furthermore, a recent study suggests that depletion of the receptor tyrosine kinase EphB2 mediates Aβ-induced NMDAR blockade (Cisséet 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-containing NMDARs may be involved in Aβ-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.

Mitochondrial ROS

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

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 Aβ and accelerated cognitive dysfunction (Li et al. 2004; Esposito et al. 2006). Conversely, it has been shown that over-expression of SOD-2 in two different AD mouse models is capable of reducing brain Aβ 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 impairments 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).

image

Figure 3.  Abnormal accumulation of Aβ 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 effects as oxidative stressors, resulting in impairments of synaptic plasticity and memory.

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Glycogen synthase kinase-3

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

Two isoforms of GSK3 exist, GSK3α and GSK3β. 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 GSK3β, and the tissue-specific distribution, cellular localization, and functions 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 GSK3β and Ser 21 in GSK3α) 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 Aβ.

Increasing evidence suggests that the relationship between GSK3 and Aβ is probably bidirectional. For example, high GSK3 activity may interfere with normal APP processing via modulation of the function of secretases, leading to Aβ 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 Aβ production and reducing plaque 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 Aβ production were specifically attributed to GSK3α and not GSK3β (Phiel et al. 2003). In contrast, Aβ can activate GSK3 through dephosporylation, which is linked to down-regulation of the PI3K/Akt signaling pathway (Magranéet 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 Aβ-induced LTP failure can be prevented by pre-treatment of brain slices with a specific GSK3 inhibitor (Jo et al. 2011). Compared with the abundance 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

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

Mammalian target of rapamycin is an evolutionarily conserved 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 different 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 pharmacological agents or genetically-modified mice, which have demonstrated that disruption of mTOR signaling results in 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 Aβ (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 Aβ. 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 therapeutically 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 downstream effector of mTOR, results in increased life span (Harrison et al. 2009; Selman et al. 2009). However, whether either hippocampal synaptic plasticity or hippocampus-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 Aβ-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 Aβ 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. Aβ was shown to impair insulin-PI3K-Akt signaling (Magranéet 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 disagreement 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

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

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 Aβ. 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

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References

This work was supported by National Institutes of Health grants NS034007 and NS047834, and Alzheimer’s Association Investigator. This review is dedicated to the memory of Dr. Mark A. Smith, a great colleague and a better friend.

References

  1. Top of page
  2. Abstract
  3. Aβ-induced memory impairment
  4. Aβ abrogates synaptic plasticity
  5. Deciphering the cellular mechanisms of Aβ-induced synaptic dysfuction
  6. NMDA receptors
  7. Mitochondrial ROS
  8. Glycogen synthase kinase-3
  9. Mammalian target of rapamycin
  10. Concluding remarks
  11. Acknowledgements
  12. Conflict of interests
  13. References