Implications of Oligomeric Amyloid-Beta (oAβ42) Signaling through α7β2-Nicotinic Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic Excitability and Cognitive Decline

Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-beta (A beta) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-beta (oA beta(42)), interacting with alpha 7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oA beta(42) activates both homomeric alpha 7- and heteromeric alpha 7 beta 2-nAChR subtypes while preferentially enhancing alpha 7 beta 2n-AChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oA beta(42) showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band and horizontal diagonal band, but not the nucleus basalis. Last, aged male and female APP/PS1 transgenic mice, genetically null for the beta 2 nAChR subunit gene, showed improved spatial reference memory compared with APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for alpha 7 beta 2-nAChR in mediating the effects of oA beta(42) on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of alpha 7 beta 2-nAChR in oA beta(42)-induced cognitive decline.

Automated summary

This study reveals the molecular mechanism behind the subnucleus-specific alterations in BFCN excitability caused by the interaction between oAβ(42) and nAChR receptors, as well as confirms the important role of α7β2-nAChR in oAβ(42)-induced cognitive decline.