7 Nicotinic Acetylcholine Receptors in Alzheimer's ... - IngentaConnect

Current Drug Targets, 2012, 13, 613-622

7 Nicotinic Acetylcholine Receptors Neuroprotective, Neurotrophic or Both?

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Caterina M. Hernandez* and Kelly T. Dineley Department of Neurology, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555-0616, USA Abstract: One of the early signs of Alzheimer’s disease is the impairment in hippocampus-based episodic memory function, which is improved through the enhancement of cholinergic transmission. Several studies suggest that 7 nicotinic receptor (nAChR) activation represents a useful therapeutic strategy for the cognitive impairments associated with early Alzheimer’s disease as the 7 subtype of nicotinic acetylcholine receptors are expressed by basal forebrain cholinergic projection neurons as well as by their targets in the hippocampus. The current model for the cholinergic deficit in Alzheimer’s disease posits that inappropriate accumulation of misfolded oligomeric aggregates of -amyloid peptide leads to the dysfunction of the signaling mechanisms that support the cholinergic phenotype; this is manifested as an altered function of nicotinic acetylcholine receptors and the nerve-growth factor trophic support system that results in the loss of cholinergic markers and eventually cholinergic neurons from the basal forebrain cholinergic system. A view was confounded by the fact that 7 nAChRs and -amyloid peptides have been shown to interact in vitro and in vivo, including human post-mortem AD brain. This review will begin with a brief overview of the basal forebrain cholinergic system, followed by a discussion of the current knowledge of the cholinergic deficit in Alzheimer’s disease, then a summary of the cholinergic phenotype observed in transgenic Alzheimer’s disease mouse models. We will also present our recent findings that support our hypothesis that the 7 nicotinic acetylcholine receptor performs both the neurotrophic and neuroprotective roles in the maintenance of the cholinergic phenotype and discusses potential mechanisms and implications for Alzheimer’s disease therapy.

Keywords: -amyloid, basal forebrain cholinergic system, hippocampus, nerve growth factor. INTRODUCTION A common feature of neurodegenerative diseases is that each presents with a unique pattern of vulnerable brain regions that exhibit the pathological hallmarks of the disease. While disruptions in other central neurotransmitter systems are also observed (e.g., serotonergic and noradrenergic), the involvement of the central cholinergic system in Alzheimer’s disease (AD) is the focus of this review [1, 2]. In early AD, there is impairment in hippocampus-based episodic memory that is improved through the enhancement of cholinergic transmission, indicating that the compromise of septo-hippocampal connectivity underlies the earliest AD symptomatology [3]. Anatomically, septo-hippocampal connectivity occurs through long cholinergic projection neurons that connect soma in the basal forebrain (a forebrain complex comprised of the nucleus basalis of Meynert, medial septum and diagonal band complex) with the neocortex, hippocampus, olfactory bulbs and amygdala. Under normal conditions, basal forebrain cholinergic projection neurons provide the major source of cholinergic innervations to these regions and play a key role in mediating attention and memory function. In AD, basal forebrain cholinergic neurons preferentially accumulate misfolded -amyloid peptide (A) and tau-

*Address correspondence to this author at the Department of Neurology, University of Texas Medical Branch, 301 University Boulevard Route 0616, Galveston, Texas 77555-0616, USA; Tel: 409-772-9620 (Desk), 409-7477063 (Lab); Fax: 409-747-7050; E-mail: [email protected] 1873-5592/12 $58.00+.00

containing neurofibrillary tangles, possibly providing an explanation for the selective vulnerability of this neuronal population [4-7]. Since the discovery that autosomal dominant mutations in the amyloid precursor protein (APP) and presenilin (PS) genes cause inherited forms of AD, several transgenic animal models based on these gene mutations have emerged that recapitulate certain features of the disease including the accumulation of misfolded A and, in some instances, tau, as well as hippocampus-dependent learning and memory deficits [8, 9]. However, one aspect of AD that is uniformly absent in these animal models is an overt cholinergic deficit with the associated cognitive deficits. Several studies indicate that coincident compromises in cholinergic activity and cognition during early AD may be mediated by the 7 subtype of nicotinic acetylcholine receptors (nAChR), suggesting that 7 nAChR activation represents a useful therapeutic strategy for the cognitive impairments associated with early AD [10-13]. For example, 7 nAChRs are expressed by basal forebrain cholinergic projection neurons and 7 nAChR activation attenuates A toxicity; in vivo, 7 nAChRs have been shown to contribute to the maintenance of the septo-hippocampal cholinergic phenotype [14-18]. However, this view is confounded by the fact that 7 nAChRs and A peptides have been shown to interact in vitro and in vivo, including post-mortem AD brain [19-23]. Nonetheless, several recent findings prompt us to argue that 7 nAChR – A interaction likely serves both a normal physiologic role and contributes to the molecular etiology of AD [23]. For example, picomolar A can amplify hippocampal long-term potentiation in young rodents via the © 2012 Bentham Science Publishers

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activation of 7 nAChRs on one hand, and yet on the other, 7 nAChR–A interaction in aged AD mouse models appears to exacerbate their pathological features [18, 24-26]. We recently tested the role of 7 nAChRs in the pathology of pre-plaque AD when early cognitive decline is underway and found in vivo evidence that, at least during early stage disease, the 7 nAChR serves a neuroprotective role by preserving the cholinergic phenotype in the basal forebrain and at least one of its projection regions, the hippocampus. Our current model for the cholinergic deficit in AD posits that inappropriate accumulation of misfolded oligomeric -amyloid (A) peptide leads to dysregulation of the signaling mechanisms that support the cholinergic phenotype (i.e. maintenance of basal forebrain cholinergic neuron numbers and marker activity); this dysfunction is manifested as disrupted 7 nAChR function and nervegrowth factor trophism [27-37]. As such, we consider the 7 nAChR to be critical for maintaining the cholinergic phenotype under conditions of excess A, such as those seen in AD, and represents an important therapeutic target in the disease. This article will: 1.

Review the basal forebrain cholinergic system (BFCS)

2.

Summarize current knowledge of the cholinergic deficit in AD

3.

Review the status of the cholinergic system in AD mouse models expressing transgenes that cause the inherited form of AD in humans

4.

Present our recent findings that support our hypothesis that the 7 nAChR performs both the neurotrophic and neuroprotective role in the maintenance of the cholinergic phenotype

5.

Discuss potential mechanisms and implications for AD therapy.

I. THE SYSTEM

BASAL

FOREBRAIN

CHOLINERGIC

Acetylcholine is an essential neurotransmitter for a variety of attentional and learning, and memory processes. In presynaptic nerve terminals, choline acetyltransferase (ChAT) synthesizes acetylcholine and the vesicular acetylcholine transporter (VAChT) is responsible for the transport of acetylcholine into synaptic vesicles for storage until exocytotic release into the synapse. The cholinergic basal forebrain (CBF), a forebrain multi-structure complex comprising of the medial septum, diagonal band of Broca and nucleus basalis of Meynert, is a major source of acetylcholine and provides the principal cholinergic innervation to the cortex, hippocampus and amygdala.

endogenous neurotransmitter acetylcholine (ACh). The metabotropic receptors are second messengers, G proteincoupled seven-transmembrane proteins [38, 39]. The other subtype of AChR is the ionotropic nicotinic receptor (nAChR). Neuronal nAChRs are differentially expressed in the central and peripheral nervous systems; each receptor subtype has characteristic pharmacological and biophysical properties. nAChRs exist as homomeric or heteromeric pentamers. In mammals, heteromeric neuronal nAChRs theoretically may exist as a combination of 12 different subunits (2–10, 2–4); however, two types of nAChR occur most abundantly in the CBF: the heteromeric 42 nAChR and the homomeric 7 nAChR. The focus of this review will be the 7 subtype of nAChRs. The nuclei of both GABAergic and cholinergic neurons are located in the BF. The cholinergic neurons project to the hippocampus, cortex, and olfactory bulbs, which are brain regions that are particularly vulnerable to the ravages of AD. 7 nAChRs are expressed within the CBF nuclei as well as pre- and post-synaptically in CBF target regions. The cholinergic deficit in AD is due in part to the altered expression of these receptors by both the CBF projection and target neurons [11, 12, 40, 41]. 7 nAChRs flux the pluripotent second messenger Ca2+ and have been shown to modulate neuron excitability, the induction of LTP, and partially mediate the cognitive enhancing effects of in vivo administered nicotine [42-46]. Nicotine has been shown to improve attention, as well as learning and memory performance in patients with mild to moderate AD, as do drugs that potentiate central cholinergic function [47-51]. In addition, several studies have reported positive effects of selective 7 nAChR agonists in a variety of cognitive tasks, suggesting the involvement of 7 nAChRs in the pro-cognitive effects of nicotine [52]. IB. Maintenance of the Cholinergic Phenotype Nerve growth factor (NGF) neurotrophic signaling maintains the cholinergic phenotype by promoting cholinergic neuron survival and plays an important role in memory and attention tasks. Lesions of the septo-hippocampal pathway are an avenue by which NGF deprivation can be induced in vivo and this leads to cholinergic hypofunction expressed as reduced ChAT activity and impaired hippocampus-dependent spatial learning and memory [53, 54]. In lesioned animals, septal infusion of NGF improves spatial memory task performance through the restoration of cholinergic activity [55, 56]. Furthermore, endogenous NGF levels also correlate with an animal’s capacity for spatial learning [57, 58]. As such, a central concept in the mechanisms underlying the maintenance of the basal forebrain cholinergic phenotype (i.e. neuronal survival and expression of cholinergic marker genes) is that NGF-mediated signaling through high-affinity TrkA and low-affinity p75 neurotrophin (p75NTR) receptors is a necessity.

IA. 7 Nicotinic Receptors in the BFCS

IB1. NGF Synthesis, Secretion

Two major subtypes of acetylcholine receptors (AChRs) are expressed in the central nervous system: the metabotropic muscarinic receptors and the ionotropic nicotinic receptors. Both share the property of being activated by the

NGF is a target-derived neurotrophin that is internalized upon binding to its receptor(s) on cholinergic nerve terminals and then packaged for retrograde axonal transport to the

7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease

cholinergic soma and nuclei in the CBF [59]. In order to exert its pro-survival and cholinergic phenotype-promoting activities, NGF must be synthesized and secreted in adequate quantity from target regions. Mature NGF is generated after cleavage at the carboxy terminus of its monomeric precursor form, proNGF [60, 61]. Thus, the secreted neurotrophin is a collective mixture of pro- and mature NGF that will potentially bind TrkA and/or p75NTR. Mature NGF binds to the TrkA receptor, which stimulates signal transduction pathways mediating the majority of the survival and growth effects of NGF, and to the p75NTR receptor which is a positive modulator of NGF/TrkA binding when it participates in a heteromeric complex with TrkA [62]. ProNGF preferentially binds to p75NTR over TrkA, leading to apoptotic death of cells co-expressing both receptors [62]. IB2: Signal Transduction Mechanisms that Promote Cholinergic Basal Forebrain Neuron Survival NGF receptor signaling activates the MAPK pathway, which participates in a wide array of biologic functions, including cell survival, synaptic plasticity, learning and memory [63]. The classic MAPK cascade involves activation of the small GTPase Ras, and the kinases Raf and MEK. Downstream consequences of MAPK activation include activation of the ribosomal S6 kinases (Rsk) and the MAPKactivated protein kinase 2 (MAPKAP2), which phosphorylates several transcription factors including Elk-1 and cAMP-regulated response element binding protein (CREB). A second downstream pathway is the PI3K/Akt pathway that also mediates neurotrophin-mediated survival [64]. As will be discussed below, NGF receptor signaling and 7 nAChR activation share these downstream mediators and supports our hypothesis that both NGF and 7 nAChRs are critical to maintenance of BFCS integrity. In contrast, the low-affinity NGF receptor, p75NTR, has multiple functions including signaling apoptosis and the activation of inflammatory pathways such as NFB [64, 65]. The particular effect of p75NTR activity is dependent upon its interaction with various receptor chaperones [66]. As well, pro-NGF binding to p75NTR homodimers can lead to apoptosis and some have postulated that A itself can bind p75NTR and signal in a likewise manner to cause CBF degenerative changes [67, 68]. II. THE CHOLINERGIC DEFICIT IN HUMANS WITH AD Since the discovery that CBF neurons are degenerated in AD patients and that treatment with cholinergic antagonists disrupts learning and memory function in humans and rodents, the cholinergic hypothesis of cognitive dysfunction has been under intense investigation [27]. An early observation in AD research and a fundamental principle for current treatment strategies is the loss of cholinergic transmission within the BFCS. Such changes during early-stage AD, are thought to be triggered by accumulating A and are associated with synaptic dysfunction and compromised cholinergic neurotransmission between the CBF and its targets in the cortex and hippocampus that manifest as episodic memory impairment [69-72]. As such, most FDA-approved drugs currently used in AD treatment are geared toward boosting acetylcholine-mediated neurotransmission [27].

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IIA. Cholinergic Function in MCI and Early AD Mild cognitive impairment (MCI) of the amnestic type has recently been identified as a prodromal form of AD based on the observation that approximately 70% of these cases convert to AD within 2-5 years [73]. As such, much attention has recently been focused on evaluating this category of patients with the hope that clinical features of MCI may shed light on the mechanisms of early AD. Despite well documented losses in ChAT activity in the later-stages of AD, cognitive deficits in MCI and early AD are not associated with a similar reduction in ChAT activity. For example, ChAT activity is preserved in the neocortex of MCI patients and recent studies have shown that ChAT activity is actually elevated in the hippocampus and frontal cortex of some MCI brains, indicating that components of the CBF projection system are capable of compensatory responses [74-76]. Mechanisms proposed to underlie this increase include sprouting in response to the loss of glutamatergic input and/or resilience of particular CBF nuclei to AD processes [77-79]. The fact that many MCI and early AD patients present with memory complaints that are improved with anti-cholinesterase treatments supports the notion that the up-regulation of ChAT activity, whether compensatory or not, represents a pathological condition. As such, preservation of at least some components of the BFCS during the early progression of dementia and positive responses reported by patients on anti-cholinesterase treatments strongly support continued use of cholinesterase inhibitor drugs as a treatment early in the onset of AD. IIB. Modulation of 7 nAChRs During Progression of AD Elucidating the molecular mechanisms that underlie the selective vulnerability of cholinergic neurons to toxicity would greatly advance our capabilities to treat the AD cholinergic deficit. The observation that A preferentially accumulates in neuronal populations that are also enriched with 7 nAChRs may provide an important clue. The upregulation of 7 nAChR mRNA and protein has been reported in astrocytes, peripheral blood leukocytes and cortical and hippocampal neurons harvested from the tissue of AD patients [22, 80-82]. In one study, mRNA expression levels of nicotinic and muscarinic AChR subtypes and ChAT were measured in single cells isolated from the CBF of postmortem AD tissue (and non-cognitively impaired controls), then individually analyzed using microarray methods. No differences in mRNA expression were observed for the other nAChR subunits, mAChR subtypes or ChAT [76]. However, cells from AD basal forebrain exhibited a significant upregulation of 7 nAChR subunit mRNAs [76]. This increase in 7 nAChR expression levels within CBF neurons was inversely correlated with Global Cognitive Score and with Mini-Mental State Examination performance [76]. As such, increased 7 nAChR may be a compensatory attempt to regulate cholinergic tone through pre- and/or postsynaptic mechanisms. Thus, 7 nAChRs, either on cholinergic projection neurons or within the neocortex of the BFCS are important for the types of cognitive performances that are impaired in early AD. An alternative interpretation is that these increases in 7 nAChR protein within the basal forebrain may be in


response to a direct interaction with A and receptor desensitization followed by receptor up-regulation. Recent studies have shown that in AD tissue, much of the 7 nAChR protein in brain regions targeted by the CBF is associated with A; disruption of this association in postmortem AD cortex leads to increased availability of functional 7 nAChRs [22]. These observations suggest that in AD, 7 nAChRs are likely inactive due to desensitization as a consequence of prolonged association with A peptide. This model of 7 nAChR desensitization is supported by some of our work investigating the consequences of an 7 nAChR – A interaction in vitro. We have found that acute exposure of organotypic slice cultures derived from hippocampus to low (picomolar) concentrations of A demonstrated that an 7 nAChR – A interaction leads to Ca2+ influx, ERK MAPK activation via PI3K that results in CREB phosphorylation through both PKA- and Rsk2dependent avenues [83-87]. Acute intermittent exposure (i.e. minutes to hours) of hippocampal slice cultures to high concentration of led to the down-regulation of ERK MAPK activity [83, 87]. Interestingly, repeated and extended exposure (i.e. over the course of days) to A up-regulated 7 nAChRs in hippocampal slice cultures was comparable to the effects of chronic exposure to nicotine [83]. Further evidence that and 7 nAChRs interact in vivo, 7 nAChRs up-regulate in cortical areas of the amyloid precursor protein (APP) AD mouse model as accumulates [83, 88]. Combined, these in vitro findings and in vivo observations suggest that physiological concentrations of impinge upon signal transduction cascades important for synaptic plasticity, learning and memory, and homeostasis. Short exposure times (minutes) and moderate concentrations (pico- to nanomolar) do not lead to permanent changes in 7 nAChR or the ERK MAPK cascade; higher doses and extended exposure time lead to dysregulation of 7 nAChR, ERK MAPK, and CREB. Under normal physiological conditions and early in the disease, 7 nAChR – A interaction likely results in transient 7 nAChR activation and downstream signal transduction cascades that promote neuronal survival and function; however, as A concentration increases, prolonged association with A leads to receptor desensitization and functional down-regulation. Thus, the observed increase in 7 nAChR expression in human AD BFCS may be a reflection of an aberrant and prolonged 7 nAChR - A interaction that eventually exacerbates into further neuronal dysfunction. IIC. NGF Signaling in AD The survival and maintenance of the cholinergic phenotype in the BFCS depends upon the availability of NGF and its cognate receptors, TrkA and p75NTR. In MCI and early AD, proNGF are highly elevated [89], suggesting that the metabolic pathways regulating the processing of proNGF are altered, likely having pivotal downstream consequences for CBF neuron survival [90, 91]. Although the processes by which pro-NGF accumulates in cortex during AD are unknown, its accumulation may promote apoptotic signaling through binding to the p75NTR receptor, to which it has a higher affinity than NGF [62]. This effect is likely further


enhanced through TrkA receptor reduction as has been observed in MCI and early AD [92]. Recently, a protease cascade that targets extracellular NGF and TrkA was reported to be up-regulated in AD and MCI brains; these changes were inversely correlated with cognitive status [93]. Collectively, this suggests that AD is associated with a metabolic failure in the NGF-signaling and degradation pathways that may have a synergistic negative effect in early AD. Although the regulatory mechanisms underlying endocytic trafficking of TrkA and p75NTR receptors from early endosomes to retrogradely transported cargo is not fully characterized, it is postulated that NGF binding to its receptor(s) activates pro-survival signaling cascades at the presynaptic locus that ultimately impinge upon the nucleus to influence target gene transcription (e.g., ChAT, TrkA; [66]. Loss of TrkA and mature NGF has obvious implications for the integrity of the BFCS during AD; the relative amount of NGF and pro-NGF may determine the physiological consequences of TrkA and p75NTR signaling as does the receptor availability [89]. III. CHOLINERGIC PHENOTYPES IN AD ANIMAL MODELS Based on the identification of autosomal dominant mutations in the APP and PS genes, as well as the concept that tau is also an important mediator of AD processes, several transgenic mouse models have been developed in the past 15 years [8, 9]. APP transgenic mouse models, either singly or in combination with PS-1 transgenes, successfully demonstrated age-dependent A accumulation, synaptic dysfunction, learning and memory deficits, and, in some cases, tau aggregation indicative of neurofibrillary tangle formation. However, robust deficits in the BFCS with accompanying CBF neurodegeneration have not been recapitulated in such models [94]. For example, the Tg2576 APP mouse model is one of the most extensively studied AD animal models yet, while this AD mouse model exhibits A over-production and accumulation, early onset (5-months-of-age) and progressive memory deficits, impaired synaptic plasticity, and alterations of several biochemical markers of proper cognitive function, cholinergic hypofunction and marked BFCS neurodegeneration are noticeably absent [83, 84, 95-103]. An alternative AD mouse model that does not depend upon the expression of an AD-related mutant human transgene but targets the NGF neurotrophic system does exhibit a profound BFCS phenotype that is lacking in other AD mouse models. This approach generated mice that express recombinant NGF neutralizing antibodies; these AD11 anti-NGF mice display deficits in cholinergic function in parallel with age-dependent neuropathology that resembles the cholinergic deficit in human AD [104, 105]. For instance, adult AD11 mice exhibit hippocampus-dependent spatial memory deficits and associated cholinergic atrophy, neuronal loss, tau hyperphosphorylation and aggregation, A deposits, and synaptic plasticity deficits [106, 107]. An intriguing and compelling aspect of the cholinergic and synaptic plasticity deficits observed in these mice is that they are accompanied by altered 7 nAChR function; suggesting that disruption of the NGF trophic signaling network leads to


dysregulation of 7 nAChR function [108]. As we will discuss below, we would also consider the possibility that 7 nAChR function likewise regulates the NGF trophic signaling network. The evidence that nAChRs perform a neuroprotective role in AD has a long and enigmatic history. Some epidemiological studies have concluded that smoking is negatively-correlated with AD incidence [109]; the fact that highaffinity nicotine binding sites (42 nAChRs) on cholinergic projection neurons are depleted in early stages of the disease indicates that these receptors are an important component of the pathophysiology of AD [40, 41]. Several studies have demonstrated that nAChR activation attenuates A toxicity; protection against toxicity is proportional to the number of 7 nAChRs expressed by cultured cells [16] and chronic exposure to A1-42 in vitro leads to the up-regulation of 7 nAChRs in a manner similar to the effects of chronic nicotine treatment [83, 88]. Tg2576 mice that produce excessive A continue to up-regulate cortical and hippocampal 7 nAChRs as these animals age, possibly providing an explanation as to why this AD model does not exhibit significant loss of cortical or hippocampal neurons [83, 88, 110-113]. Based on the plethora of evidence from a variety of approaches that 7 nAChRs are particularly important for neuroprotection from A toxicity, we recently tested the hypothesis that 7 nAChRs are neuroprotective during early stage AD by investigating the effects of 7 nAChR gene deletion on cognitive function and septo-hippocampal integrity in the Tg2576 APP transgenic animal model for AD [114]. IV. THE A7KO-APP MOUSE MODEL FOR AD EXHIBITS A PRONOUNCED CHOLINERGIC PHENOTYPE (TABLE 1) Whereas 7 nAChR knocked-out (A7KO) mice neither show cognitive deficits nor exhibit morphological CNS abnormalities, we found that cognitive deficits seen in 5month-old APP transgenic mice are more severe when 7 nAChR receptors are absent (A7KO-APP) [114-116]. Biochemical analyses on 5-month-old A7KO-APP revealed a significant reduction in hippocampal and basal forebrain ChAT activity and loss of hippocampal neurons and markers; stereological analyses indicated more pronounced loss of hippocampal pyramidal neurons and volume loss compared to APP mice. Consistent with lesion studies and observations in AD brain, the compromise of basal forebrain cholinergic function leads to similar concessions within the hippocampus of 5-month-old A7KO-APP mice supporting the notion that the compromise of basal forebrain cholinergic neurons is the underlying mechanism for ChAT reduction in A7KO-APP hippocampus. However, the fact that A7KO mice exhibit a loss of ChAT activity in basal forebrain with no effect on hippocampal ChAT indicates that the added stress of excess A in conjunction with loss of 7 nAChRs is necessary to induce such changes in 5-month-old A7KOAPP animals. These studies demonstrated that 7 nAChRs mediate neuroprotective mechanisms that maintain the septohippocampal cholinergic phenotype and preserve hippocampal integrity; loss of BFCS integrity is accelerated and


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exacerbated when 7 nAChRs are absent and misfolded A is in excess. Table 1. Comparison of AD APP Mouse Models Feature

AD

Other AD-APP

A7KOAPP

A7KO-APP Phenotype

Cognitive Deficits

X

X

X

HIP-dependent learning

Neuron Loss

X

--

X

HIP neuron number (CA3) & volume (CA3/DG)

A oligomer accumulation

X

X

X

Accumulation of dodecamers in HIP

Cholinergic Hypofunction

X

--

X

HIP and BF ChAT activity

X

HIP ERK and MAP2 activity

Other

Abbreviations: hippocampus (HIP), CA3 subregion of HIP (CA3), Dentate gyrus (DG), basal forebrain (BF), choline acetyltransferase (ChAT), extracellular signal-related kinase (ERK), microtubule-associated protein (MAP).

The A7KO-APP mouse model serves as a useful system to study the interplay of the NGF neurotrophic system and loss of 7 nAChR function on BFCS integrity and maintenance of the cholinergic phenotype during AD-like accumulation of misfolded A. As such, we are currently investigating the status of the NGF neurotrophic system in the CBF and its target regions of A7KO-APP animals. We can report preliminary results that the NGF trophic system is indeed coincidentally compromised with the loss of BFCS system integrity, providing additional evidence that 7 nAChR and NGF signaling are somehow interconnected (unpublished results). One possible mechanism by which these two systems are related is suggested by a recent publication in which it was reported that CBF electrical stimulation leads to increased NGF in parietal cortex microperfusate that is blocked by the general nAChR antagonist, mecamylamine [117]. Perhaps, 7 nAChRs support the cholinergic phenotype through direct effects on the NGF secretion from CBF projection neuron targets. V. POTENTIAL MECHANISMS AND IMPLICATIONS FOR CURRENT AND FUTURE THERAPEUTIC STRATEGIES Activation of the PI3K pathway may mediate neuroprotective mechanisms through the stimulation of nAChRs. Several lines of evidence suggest that this can occur through transactivation of src and tyrosine kinase receptors, including the high-affinity NGF receptor, TrkA [14, 17, 118-120]. Paradoxically, at low to moderate (i.e. physiological and non-disease) concentrations of soluble A1-42, PI3K is also activated, suggesting that an 7 nAChR - A interaction can lead to the activation of neuroprotective mechanisms [87]. In vitro and in vivo, chronic nicotine leads to an increase in TrkA receptor protein, as well as 7 and 42 nAChRs; in vivo, this is accompanied by the up-regulation of ChAT and VAChT in hippocampus [120-122]. Increased TrkA is neuroprotective against A toxicity; high concentrations of



underway and found in vivo evidence that, at least during the early stage disease, the 7 nAChR serves a neuroprotective role by preserving the cholinergic phenotype in the basal forebrain and at least one of its projection regions, the hippocampus. In contrast to a neuroprotective role in early AD, we hypothesize that 7 nAChRs may actually contribute to the pathology of late-stage AD through deleterious effects on synaptic integrity, cholinergic functionality, and cognition. In support of this notion is a recent study in which deletion of 7 nAChRs from the PDAPP mouse model led to an improvement in cognition in aged (13-22 months) mice.

A are neurotoxic and block nicotine-induced TrkA upregulation [17, 120]. Additionally, these studies suggest that in a situation of excess A, the trophic activity is challenged by the inhibition of nAChR function, further contributing to A toxicity. Thus, the stimulation of nAChRs promotes neuroprotective mechanisms crucial for the maintenance of cholinergic neuron integrity by facilitating trophic TrkA receptor signaling through the stimulation of signal transduction pathways that support neuron survival. Based on several recent findings, we would argue that 7 nAChR – A interaction likely serves both a normal physiologic role and contributes to the molecular etiology of AD [23]. One might imagine that under normal physiologic conditions, an 7 nAChR - A interaction itself can serve as a trophic signal. However, as A accumulates, this interaction disrupts nAChR-mediated trophism and/or mediates mechanisms that induced neurotoxicity. For example, recent work suggests that picomolar A can amplify hippocampal long-term potentiation in young rodents via the activation of 7 nAChRs; however, 7 nAChR – A interaction in aged AD mouse models may exacerbate their pathological features [18, 24-26]. In fact, 7 nAChR-selective agonists are unable to activate these receptors in APP transgenic mice and a recent work on human AD postmortem tissue indicates that much of the receptor protein is functionally inactivated due to the association with A peptide [18, 22, 25].

Based on the current understanding, we propose that in the early stages of AD, the appearance of soluble A oligomers is a crucial triggering event leading to the transient activation of 7 nAChRs and subsequent initiation of both neuroprotective and neurotrophic signaling mechanisms that parallel those stimulated by NGF-TrkA interaction (Fig. 1). Through binding and sequestering A oligomers, the neuroprotective effects of activating 7 nAChRs are initiated as it (possibly) sequesters and prevents further oligomerization, thus deviating A from additional toxic interactions (e.g., mediators of glutamatergic neurotransmission; [123, 124]. As AD progresses, we envision that A accumulates and irreversibly associates in a manner that overwhelms the availability of 7 nAChRs leading to functional blockade. This model may explain in part the limited therapeutic window for the use of cholinesterase inhibitors in AD therapy.

We recently tested the role of 7 nAChRs in the pathology of pre-plaque AD when early cognitive decline is

monomer

1 A

A

A

A

Other Toxic Effects

3 (-)

oligomer

4 2

NGF 7

7

7

PI3K ERK

Neuroprotection

phospho-TrkA

Cholinergic yp Phenotype

Fig. (1). A model for 7 nAChR neuroprotection in early AD. 1. A monomers aggregate to form oligomers. 2. A oligomers bind 7 nAChR. 3. At low concentrations, A oligomer assemblies can activate 7 nAChRs leading to PI3K and ERK MAPK activation that couples to neuroprotective signaling and maintenance of the cholinergic phenotype in a manner that parallels NGF neurotrophic signaling. 4. The high-affinity interaction between A and the 7 nAChR leads to prolonged association thereby retarding further A oligomerization as well as preventing toxic interactions with other A targets.


In general, long-term clinical assessments indicate that the main effect of anticholinesterase drugs is the symptomatic treatment with limited disease modifying actions [125]. Since the cholinergic deficit is not an early defect in the progression of AD [74-76], the use of these drugs in the prodromal stages of AD should be continued. However, the limited effect of cholinesterase inhibitors for the treatment of cognitive decline in AD poses a significant clinical challenge. We hypothesize that the interaction between 7 nAChRs and A peptides during AD progression may hold the key. Our model, discussed in the previous section, posits that A acts as an endogenous ligand for 7 nAChRs under normal physiological conditions and this interaction leads to a transient activation of the receptor and the stimulation of pro-survival signal transduction pathways (e.g., PI3K, ERK) and maintenance of the basal forebrain cholinergic phenotype in a manner quite similar to NGF. In fact, we further hypothesize that the BFCS 7 nAChR and the NGF trophic signaling populations are interconnected. At present, it is not feasible to confidently predict the appropriate 7 nAChR therapeutic strategy in AD; much still needs to be understood about 7 nAChR – A interaction during the initiation and progression of AD. Nonetheless, one might consider a few possibilities, depending on the outcome of key future clinical studies. For example, one might advocate for the development and use of 7 nAChR compounds that prevent or reverse A receptor binding in order to resurrect 7 nAChR function and its neuroprotective properties. Several 7 nAChR agonists and positive allosteric modulators (PAMs) have been developed as therapeutic agents targeting central and peripheral disorders that involve pain, inflammation, schizophrenia, and AD [126-128]. One such compound, S-24795, was recently directly tested for efficacy in AD; application to homogenates prepared from post mortem AD brain was found to facilitate A dissociation from the receptor in order to resurrect 7 nAChR function and its neuroprotective properties [22, 36]. Possibly, S-24795, and other such 7 nAChR PAMs would prove beneficial during early AD by both inhibiting and partially reversing the A binding to 7 nAChRs. However it remains to be seen if the dislodged A is then free to interact in alternative yet deleterious ways. Possibly, coincident A immunotherapy would alleviate this potential negative side effect of 7 nAChR PAM therapy. Another possible strategy, albeit somewhat difficult to envision at the receptor level, would be to develop a compound that is capable of maintaining 7 nAChR neuroprotective signaling capabilities on the one hand and continue to sequester A on the other. Again, this in conjunction with interventions that decrease oligomeric A levels might prove most efficacious. An 7 nAChR – A interaction was first described over a decade ago. Initial studies reported seemingly incongruent consequences of this interaction such as receptor antagonism versus activation [21, 23]. As we delve deeper and refine our understanding of this interaction and how it relates to the pathophysiology of AD progression, it is evident that A effects on 7 nAChRs are quite dynamic and, at minimum, depend upon the concentration and aggregation state of A which may have profound effects on receptor responsivity which, in turn, may have profound effects on the responsivity of the NGF neurotrophic signaling network.


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Revised: June 25, 2011

PMID: 22300028

Accepted: July 01, 2011