A Novel, α7β2-nicotinic Acetylcholine Receptor In Forebrain Cholinergic Neurons Is Highly Sensitive To Amyloid-beta Peptides

Alzheimer's disease (AD) is considered to be the most common dementing, neurodegenerative disorder, and it is characterized by increased accumulation of amyloid beta (Aβ) peptides, degeneration of forebrain cholinergic neurons, and learning and memory disabilities. Although understanding of this disorder has greatly advanced over the past few years, the precise pathogenic mechanisms remain uncertain. Anti-AD effects of nicotinic acetylcholine receptor (nAChR) activity are suggested by evidence of nAChR-mediated attenuation of Aβtoxicity and amyloid plaque formation in vitro and in vivo, activation of bothα-secretase and ACh release, facilitation of Aβinternalization, inhibition of MAPK/NF-κM/c-myc signaling reduction of Aβproduction, and attenuation of tau phosphorylation. Conversely, Aβ-mediated inhibition of nAChR function, particularly of nAChRs on forebrain cholinergic neurons, could be an early and critical step in Ap toxicity and AD etiopathogenesis. However, although forebrain cholinergic neurons degeneration is shown as a key pathological feature of AD, it remains not-yet-defined that whether and how pathologically-relevant levels of Aβ(from pM to nM), could impair cholinergic transmission or even induce neuron degeneration. The central hypothesis of this project is that a novel nAChR form, postulated to be a heteromericα7β2-nAChR on forebrain cholinergic neurons, is highly and selectively susceptible to functional blockade by pathologically-relevant concentrations of Ap. Two major steps have been made to test this hypothesis. Step 1: Define the functional, pharmacological and molecular properties of the novel form of nAChR found on forebrain cholinergic neurons and confirm these properties using heterologously expressed nAChRs with known subunit composition. Step 2: Determine whether novelα7β2-nAChRs (naturally and heterologously expressed) are particularly sensitive to functional blockade by pathologically-relevant concentrations of Aβ. Relevant nAChR function and structure were characterized using electrophysiological, molecular biological and immunocytochemical approaches in rats, in wild-type or nAChRβ2 subunit knockout mice, and in a Xenopus oocyte expression system. Results from the above steps support the central hypothesis that a novel, heteromericα7β2-nAChR exists on basal forebrain cholinergic neurons and it is a sensitive target of pathology-relevant concentration of Aβ. This finding represents a potential breakthrough in understanding how Aβpeptides impair cholinergic transmission and harm forebrain cholinergic neurons in AD. The significance of this research also lies in the potential to illuminate processes that could occur early in AD and thus might be targets for early interventional therapies. Briefly, functional blockade of this novel nAChR form (α7β2-nAChR) could be an early and critical event in Aβneurotoxicity and AD etiopathogenesis. High sensitivity of this nAChR, particularly given its location on forebrain cholinergic neurons, to Aβcould lead to broad disruptions in chemical signaling characteristic of AD. Drugs targeting this novel nAChR could be viable tertiary or even primary therapies for AD.