TEN Nicotinic Cholinergic Mechanisms in Alzheimer ' s Disease

Alzheimer's disease (AD) is a neurodegenerative condition characterized by increased accumulation of Aβ and degeneration of cholinergic signaling between basal forebrain and hippocampus. Nicotinic acetylcholine receptors (nAChRs) are important mediators of cholinergic signaling in modulation of learning and memory function. Accumulating lines of evidence indicate that a nAChR subtype, α7 receptor (α7-nAChR), plays an important role in modulations of excitatory neurotransmitter release, improvement of learning and memory ability, and enhancement of cognitive function. Importantly, the expression and function of α7-nAChRs is altered in the brain of AD animal models and AD patients, suggesting that this nAChR subtype participates in AD pathogenesis and may serve as a novel therapeutic target for AD treatment. However, the mechanisms underlying the role of α7-nAChRs in AD pathogenesis are very complex, and either neuroprotective effects or neurotoxic effects may occur through the α7-nAChRs. These effects depend on the levels of α7-nAChR expression and function, disease stages, or the use of α7-nAChR agonists, antagonists, or allosteric modulators. In this chapter, we summarize recent progresses in the roles of α7-nAChRs played in AD pathogenesis and therapy. International Review of Neurobiology, Volume 124 # 2015 Elsevier Inc. ISSN 0074-7742 All rights reserved. http://dx.doi. org/10.1016/bs.irn. 2015.08. 002 275 1. HOMOMERIC AND HETEROMERIC α7-nAChRs Nicotinic acetylcholine receptors (nAChRs) are prototypical members of the ligand-gated ion channel superfamily of neurotransmitter receptors. nAChRs represent both classic and contemporary models for the establishment of concepts pertaining to mechanisms of drug action, synaptic transmission, and structural/functional diversity of transmembrane signaling molecules (Albuquerque et al., 1997; Gotti, Carbonnelle, Moretti, Zwart, & Clementi, 2000; Lindstrom, 1996; Lukas et al., 1999). nAChRs are found throughout the body (e.g., in muscle, autonomic and sensory ganglia, and the central nervous system, CNS) (Albuquerque et al., 1997; Gotti et al., 2000; Lindstrom, 1996; Lukas et al., 1999). They exist as multiple, diverse subtypes composed as pentamers of unique combinations from a family of at least 17 (α1–α10, β1–β4, γ, δ, ε) similar, but genetically distinct, subunits (Champtiaux et al., 2003; Dajas-Bailador & Wonnacott, 2004; Fucile, 2004; Shen & Yakel, 2009). There are two major subtypes of nAChRs in the CNS. One subtype is the heteropentamers containing two or more different α or β subunit, for example, α4β2-nAChRs (Cooper, Harkness, Baker, & Millar, 1999; Nashmi et al., 2003; Scholze et al., 2011). Another is the homomeric, neurotoxin-binding, functionally versatile α7-nAChR. α7-nAChRs have been known to exist for many years based on their ability to bind the curare-mimetic neurotoxin, α-bungarotoxin (Bgt; Clarke, 1992; Sargent, Bryan, Streichert, & Garrett, 1991; Sargent & Garrett, 1995; Schmidt & Freeman, 1980). They have long been shown to exhibit many of the biochemical and pharmacological features of true nAChRs, to have brain distributions subor perisynaptic to cholinergic terminals, to have levels of expression sensitive to chronic nicotine exposure and/or modification of cholinergic inputs, and to reveal hints of functional significance in electrophysiological studies (Clarke, 1992; Sargent et al., 1991; Sargent & Garrett, 1995; Schmidt & Freeman, 1980). However, their physiological relevance was elusive and their functional study was confounded until heterologous expression studies of α7-nAChR homomers revealed unusually rapid, agonist-induced, calcium ion-permeable channel opening and inactivation (Couturier et al., 1990; Seguela, Wadiche, Dineley-Miller, Dani, & Patrick, 1993). Subsequently, renewed searches for functions of natural Bgt-binding nAChRs uncovered short-lived, nicotine-gated, toxin-sensitive, inward currents and/or elevations of intracellular Ca in chick autonomic neurons (Franceschini et al., 2002; Liu, Xie, Emadi, 276 Jianxin Shen and Jie Wu