Previous observational studies investigating Alzheimer’s disease (AD) have focused on correlating neuritic changes (plaques and tangles) with cognitive decline, with many findings questioning the translational importance of insoluble Aβ deposits in early memory loss. More recent studies have emphasized the role of soluble (e.g. oligomeric) forms of Aβ as a crucial trigger in AD-related pathologic change. Specifically, the goal of our laboratory is to understand how soluble, oligomeric forms of Aβ can modulate novel cellular mechanisms that mediate neuronal and network-level excitability, and thus neural stability. Furthermore, we seek to elucidate the functional interaction between Aβ and nicotinic acetylcholine receptors (nAChRs) and how this interaction can alter neuronal and network-level excitability. With this growing appreciation of the roles played by nAChRs in mediating the effects of Aβ excitability and human neurodegenerative disease, we seek to address the following fundamental questions:
- What specific nAChRs subtypes confer high-affinity Aβ-nAChR interactions?
- What are the underlying active and/or passive cellular processes (altered by Aβ-nAChR interactions) that contribute to neuronal instability in populations of neurons that selectively degenerate early in AD?
- What are the local excitatory and inhibitory neural circuits that influence Aβ-induced enhancement in neuronal intrinsic excitability?
- What are the behavioral correlates associated with Aβ-induced neuronal instability?
Multidisciplinary experimental approaches in nAChR neuropharmacology, in vitro electrophysiology, and models of animal behavioral have allowed us to establish, for the first time, a framework to understand Aβ mechanisms of modulation of α7*-nAChRs (*including differential subtypes) in individual neurons and integrated circuits affected early in AD. By investigating and comparing the cellular and circuit-level mechanisms altered by Aβ/nAChR interactions in both easily controlled ex vivo models of Aβ overexpression and a face-valid, well-established behavioral models of AD, our work seeks to provide novel insights and an essential foundation for future scientific and clinical work in neurodegenerative disease.
Because these mechanisms are potentially shared across other amyloidogenic diseases, our studies may define a common thread spanning multiple neurodegenerative diseases. This shared mechanism could then be targeted for therapeutic intervention by, e.g., manipulating Aβ/α7* nAChR interactions directly or through intervention of newly-defined downstream pathways altered by these interactions.