Investigating the Neuronal and Network-Level Mechanisms Underlying Alzheimer’s Disease

Dr. Andrew George is an assistant professor of Pharmacology and Toxicology at the Virginia Commonwealth University.

Alzheimer’s disease (AD) is a neurodegenerative condition that progressively destroys memory and cognition, exacting devastating personal and public health costs. Recent evidence indicates that soluble oligomeric Aβ42 (oAβ42) begins accumulating in the human brain one to two decades before clinical symptoms of AD emerge. Multiple studies suggest that elevated levels of soluble oAβ42, rather than insoluble Aβ plaques, drive the selective degeneration of vulnerable neurons and serve as the strongest predictors of cognitive decline in AD. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable to functional modulation by oAβ42, and their dysfunction has been implicated in memory loss and cognitive impairment. In septo-hippocampal pathways, α7-containing nicotinic acetylcholine receptors mediate synaptic transmission and neuronal intrinsic excitability. While most α7 nicotinic acetylcholine receptors (nAChRs) are homomeric, α7β2-containing nAChRs are preferentially expressed on BFCNs. Using single-channel electrophysiology, we show that oAβ42 activates both α7- and α7β2- nAChR subtypes, with a preferential enhancement of α7β2-nAChR single-channel open dwell times. In parallel, current-clamp recordings from BFCNs in organotypic slice cultures prepared from male and female ChAT-EGFP mice demonstrate that chronic exposure to pathophysiologically relevant levels of oAβ42 enhances BFCN intrinsic excitability. These effects are associated with reduced afterhyperpolarization and altered rates of membrane depolarization and repolarization. Mechanistically, we find that oAβ42-α7β2 nAChR interactions enhance BFCN excitability through modulation of BK-, SK-, and KCNQ/Kv7 (M-type) potassium channels. Together, these findings identify α7β2-nAChRs and downstream potassium channel targets as potential therapeutic targets for preventing BFCN dysfunction and cognitive decline in AD.

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Hosted by Dr. Harold Zakon

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