Mapping and Manipulating Cholingeric Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease

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PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. Primary pharmaceutical interventions for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, are capable of temporarily improving cognitive function, but no current treatments exist to halt or reverse AD progression. Several histopathological hallmarks manifest in AD patients, including formation of extracellular Aβ plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain cholinergic neurons (BFCNs). This marked BFCN degeneration is believed to be a major underlying cause of the cognitive deficits observed in human AD patients throughout disease progression. This supplemental application proposes to utilize tools and information garnered through current research being conducted the parent award “Genetically dissecting cholinergic signaling in body weight control” (R01DK109934), where we have selectively targeted basal forebrain cholinergic neurons for genetic manipulations and biological analysis, to elucidate either their involvement in AD. We will specifically investigate if BFCNs contribute to AD progression with their loss, or provide potential neuroprotective avenues with activation.