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 (Aß) plaques. ß-secretase-1 (ß-site APP cleaving enzyme 1, BACE1) is the rate-
limiting enzyme of toxic Aß 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.