Deciphering the selective vulnerability of basal forebrain cholinergic neurons to tauopathy

Project Summary/Abstract Selective neuronal vulnerability is a key feature of Alzheimer’s disease (AD), which also presents with other pathological features such as accumulation of intracellular neurofibrillary tangles and extracellular amyloid- β deposits. It has been known for decades that the basal forebrain cholinergic neurons (BFCNs) are severely affected in AD and highly vulnerable to early tau accumulation. The molecular mechanisms underlying pathophysiologic changes in BFCNs remain largely understudied. An overarching goal of this proposal is to reveal the interplay between tau pathology and cholinergic dysfunction, two key pathological features during the progression of AD. We will test the hypothesis that pathological tau causes BFCN dysfunction, which leads to altered cholinergic modulation of cortical function. By leveraging human induced pluripotent stem cell (iPSC)- derived BFCNs and a novel mouse model with restricted tau expression in BFCNs, we will assess the molecular and functional impacts of pathological tau accumulation in BFCNs at the neuronal, network, and animal levels. Knowledge obtained through the proposed study should have broad implications for clarifying tau pathogenesis in cholinergic dysfunction and degeneration, and inform potential therapeutics to improve the resilience of BFCNs to treat AD and related tauopathies. Research Projects: In this proposal, we will first investigate the biochemical underpinnings and functional alterations of BFCNs with pathological tau accumulation using an iPSC-derived cell model in Aim 1. Subsequently, Aim 2 will systemically examine tau spreading from the nucleus basalis BFCNs to their projected cortical areas, which may be modulated by age, tau species and neuronal activity, using a mouse model with restricted BFCN tau expression. Lastly, Aim 3 will assess the cholinergic modulation of cortical function, as well as behavioral outcomes in the mouse model with tau accumulation in nucleus basalis BFCNs. These experiments will help to dissect the molecular pathways that are altered in nucleus basalis BFCNs with tau pathology, and elucidate the functional consequences of tau accumulation in these BFCNs. Candidate Development and Environment: The training plan outlines the approaches that the candidate will employ to engage the rich resources available in her laboratory and the neuroscience community at NYU Langone Medical Center. During the K award, the candidate will expand her expertise in cellular and molecular neuroscience, in vitro disease modeling, and functional studies. Additionally, she will gain expertise in proteomics, animal behavioral assessment, and in vivo brain circuitry studies. The candidate has assembled a diverse team of mentors, advisors and collaborators for the proposed project. This will ensure successful completion of the studies by leveraging her unparalleled environment and resources. Overall, this project will ultimately enhance the candidate’s career goal of building an independent research program to study the pathogenesis of AD and develop effective therapeutics to treat this disease.