Alzheimer's disease (AD) is a neurodegenerative condition characterized by relentlessly progressive cognitive decline. There is no cure or effective treatment, especially given futility in preserving cognitive function in AD patients using interventions to remove amyloid-ß (Aß) plaques previously considered to be pathological hallmarks of disease. However, attention has turned to potential etiopathogenic roles of soluble, oligomeric forms of Aß (oAß). Moreover, remaining relevant is the loss of basal forebrain cholinergic neurons (BFCN) that provide widespread innervation to other brain centers critical for normal cognitive performance. A long-term goal of our work related to AD is to identify seminal and early disease processes that lead to BFCN functional instability and degeneration and can be targeted early enough to slow or stop neuronal death and memory compromise. Our preliminary findings support and merge aspects of both the oAß and cholinergic hypotheses of AD. They show that sustained exposure in murine organotypic culture to oAß causes hyperexcitation and eventual death of BFCN. These effects are blocked by antagonists of nicotinic acetylcholine receptors containing a7 subunits (a7*-nAChR). They also are absent for BFCN from nAChR ß2 subunit knock-out mice. nAChR a7 and ß2 subunits are enriched in BFCN where they combine to form a unique a7ß2-nAChR subtype distinct from homomeric receptors composed of a7 subunits alone (a7-nAChR). Furthermore, deficits in spatial reference memory in an AD mouse model is normalized if those mice also lack ß2 subunits. Most critical to this exploratory R21 project is our finding that oAß mimics acetylcholine (ACh) in the ability to activate a7- and a7ß2-nAChR single channel function. oAß, but not ACh, uniquely alters single channel kinetics only for a7ß2-nAChR. These studies support the project's overarching hypothesis that oAß action at a7ß2-nAChR leads to observed instability and demise of BFCN and ultimate cognitive compromise. This developmental project's goals are to identify sites for oAß:a7ß2-nAChR interactions and ways to prevent them without perturbing natural activation of a7ß2-nAChR by ACh. Specific Aim 1 is to test the hypothesis that the site for human oAß stimulation of human a7ß2-nAChR function is different than that for ACh action as an agonist. Specific Aim 2 is to test the hypothesis that fragments of Aß can block effects of oAß at a7ß2-nAChR while leaving ACh agonist action intact. Our proven skills will be used in nAChR expression, site-directed mutagenesis, pharmacology, and single channel electrophysiology. Results will provide a molecular description of oAß:a7ß2-nAChR interactions that lead to BFCN demise and could explain the emergence of dementia. These events occur early enough in disease progression to allow for novel therapeutic interventions to prevent or abate neuronal loss and useful, timely treatment of AD.