The role of beta-secretase 1 (BACE1) in modulating excitatory synaptic and circuit function and behavior - PROJECT SUMMARY Alzheimer’s Disease (AD), the most common cause of dementia, is a debilitating disease that leads to progressive memory loss, cognitive impairment, and ultimately death. Pathological hallmarks of AD include extracellular amyloid beta (Aβ) plaques. β-secretase-1 (β-site APP cleaving enzyme 1, BACE1) is the rate- limiting enzyme of toxic Aβ generation. Transgenic BACE1 KO mouse models of AD led to suppression of AD pathology, which suggests that inhibiting BACE1 may be a rational strategy for AD treatment. However, human clinical trials have shown that BACE1 inhibitors are inefficacious, even worsening cognitive function, among AD patients. This benchtop-to-bedside translational failure is due to our incomplete understanding of BACE1’s physiological function. In particular, the mechanisms underlying neuronal and synaptic impairments in BACE1 deficiency or inhibition is poorly understood. In this proposal, we will address this knowledge gap by testing the hypothesis that BACE1 modulates intrinsic and synaptic neurophysiological properties in a cell-type- and circuit- specific manner in the hippocampus, a major substrate of memory storage derailed by AD. My preliminary data of whole-cell patch clamp of hippocampal pyramidal neurons (PNs) show that selective BACE1 deletion in excitatory neurons leads to neuronal hyperexcitability, suggesting that BACE1 deletion disrupts intrinsic neuronal function in a cell-autonomous manner. Given my preliminary findings, I hypothesize that BACE1 modulates excitability and synaptic transmission in hippocampal PNs by the regulation of ion channels – the identities of which have yet to be fully elucidated. In Aim 1, I will comprehensively determine the ionic basis underlying the hyperexcitability phenotype in my Excitatory-BACE1-KO mice (mice in which BACE1 is selectively deleted in excitatory PNs), and characterize the synaptic transmission and plasticity deficits in Excitatory-BACE1-KO, through patch clamp electrophysiology methods. In Aim 2, I will delineate behavioral deficits Excitatory-BACE1- KO neurons, and rescue hypothesized cognitive deficits in mutant mice by normalizing PN hyperexcitability through a chemogenetic approach. The findings from this study will provide insight into neuronal and synaptic physiology, mechanisms of learning/memory and behavior, and future AD therapeutic strategies. Importantly, completion of this project will help me master current concepts and state-of-the-art techniques in patch clamp electrophysiology, behavior studies, and in vivo genetic perturbation and increase my scientific communication skills through extensive opportunities to present and publish my studies. As an MD/PhD student at UConn Health, I will have access to mentors and experts that will not only directly facilitate my mastery of the necessary technical skills, but I will also have opportunities to continue honing my clinical skills and gain specialized experience during and after my research phase. Fulfilling my training and development plan will be a crucial step toward my future career as a physician-scientist studying the mechanisms underlying neurodegenerative disease in patients.
