Alpha7 neuronal nicotinic receptors: The missing link to understanding Alzheimer's etiopathology?

Evidence supports the premise that Alpha7 nicotinic acetylcholine receptors in the central nervous system, sometimes referred to as neuronal nicotinic receptors (NNRs), play a central role in the development of Alzheimer's disease (AD) pathophysiology. Moreover, these receptors may represent the key to unifying aspects of the cholinergic hypothesis of AD with many of the apparently disparate mechanisms such as beta-amyloid deposition, tau hyperphosphorylation, and ApoE4 abnormalities variously proposed to underlie the progression of the disease. We hypothesize that neuronal degeneration in incipient AD is the result of coincident events involving, at their core, deficits in Alpha7 NNR function. The resulting hypocholinergic tone could potentially have serious consequences since Alpha7 NNRs are known to modulate fundamental pathways involved in cell survival such as JAK2-STAT3. This hypothesis predicts that any factors that compromise Alpha7 function have the potential to negatively impact neuronal viability. For example, such factors could include deficits in the primary neurotransmitter acetylcholine (ACh), underactivity of normal cognitive processes that stimulate Alpha7 NNRs (i.e., use-dependency), or the reported binding of beta-amyloid and ApoE4 to Alpha7 NNRs, all of which could effectively decouple the receptors from key pro-survival pathways. Since these pathways are known to negatively modulate GSK-3 beta, which regulates tau phosphorylation, downstream effects such as tau hyperphosphorylation would be expected to arise. Conversely, the maintenance of normal Alpha7 NNR activity by adequate levels of ACh or other NNR agonists would be expected to support normal cholinergic tone, prevent the binding of beta-amyloid and ApoE4 and preserve the integrity of the neurons. We therefore propose that decreased cholinergic tone is at the apex of AD pathophysiology, with factors such as beta-amyloid and ApoE4 playing a contributory role rather that a causal one and hyperphosphorylation of tau representing a detector of concomitant hypocholinergic tone and beta-amyloid deposition. Thus the convergence of beta-amyloid deposition and/or ApoE4 binding and co-localization with Alpha7 NNRs, which are favored under conditions of low cholinergic tone, and the downstream cascade of tau hyperphosphorylation through disinhibition of GSK-3 beta appear to explain and reconcile many of the discordant findings in this very active area of CNS research. (C) 2009 Elsevier Ltd. All rights reserved.