PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. The most effective interventions for AD are pharmaceuticals that include acetylcholinesterase inhibitors, which prevent the degradation of acetylcholine. While these treatments are capable of temporarily improving the symptoms of disease, they do not halt or reverse AD progression. Several histopathological hallmarks have been associated with AD, including formation of extracellular Aβ plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain neurons (the primary source of acetylcholine in the brain). This marked degeneration of the basal forebrain has been observed in human AD MRI studies and typically indicates the advent of early disease. In fact, the degeneration of acetylcholine projecting, or cholinergic neurons in this region that is believed to be an important underlying cause of the cognitive deficits that emerge as disease progresses. However, human studies are limited, as we are not able to examine brain degeneration with cell type specificity using currently available imaging modalities. This highlights an important gap in our understanding of AD: it is unknown whether basal forebrain cholinergic neuron (BFCN) degeneration occurs in an organized manner, nor how the extent of this degeneration correlates to cognitive deficits. Therefore, further investigation of BFCNs in the context of AD is needed. This leads to our central hypothesis: that BFCN signaling is adversely altered in a consistent temporal and spatial pattern, and that stimulating BFCN activity will mitigate cognitive symptoms. The overarching goal of this project is to better characterize BFCN signaling in the pathological context of AD. This will be examined through two primary aims, both of which utilize the 5xFAD model of AD, a transgenic mouse model known for rapid manifestation of the AD phenotype and has been shown to exhibit BFCN degeneration. Experiments proposed in Aim 1 will investigate longitudinal alterations in BFCN circuitry by leveraging myriad targeted cellular manipulations to perform in vivo fMRI of BFCN functional connectivity in awake mice, and to generate a timeline of molecular profiles for BFCNs using TRAP-seq. Aim 2 will explore how artificially stimulating and silencing BFCNs influences cognitive function in the context of AD. Together, these data will further our understanding of BFCN degeneration in AD and better define the roles of BFCNs in cognition.

Narrative While the degeneration of basal forebrain cholinergic neurons (BFCNs) is a well-known feature of Alzheimer’s Disease, the pattern of degeneration and the extent to which this phenomenon contributes to cognitive decline remain elusive. The research proposed here seeks to define how the neural circuitry associated with BFCNs is altered throughout Alzheimer’s Disease progression and aims to evaluate the effects of targeted, cell-type specific manipulations of BFCNs. Studies such as this are essential to further our understanding of the circuit pathology underlying Alzheimer’s Disease and identify potential therapeutic targets.