The membrane-bound aspartic protease 13-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the 13-secretase enzyme that generates the first cleavage in the formation of the 13-amyloid (AI3) peptide from APP (1). Thus, BACE1 is a prime therapeutic target for Alzheimer's disease (AD). However, BACE1 inhibitors with drug-like properties that cross the blood-brain barrier (BBB) have proven difficult to develop. Although the first BBB-penetrant BACE1 inhibitors are currently entering clinical trials in humans, we are still years away from knowing whether any will be successful in treating or preventing AD. Meanwhile, it is of paramount importance to study the cell biology of BACE1 to fully elucidate its mechanism of action in Al3 generation, for deep understanding of factors that regulate BACE1 trafficking and access to APP substrate in neurons of the brain may uncover novel, effective, and practical AD therapeutic targets.
The current proposal aims to elucidate the roles of Eps homology domain (EHD) proteins and synaptic activity in BACE1 axon transport in the brain and is linked to the application of our collaborator Dr. Gopal Thinakaran (U. Chicago) to determine the function of EHD proteins in Al3 production and amyloid deposition in vivo. EHD proteins regulate dynamic BACE1 axon transport in primary hippocampal neurons in vitro (manuscript in preparation). In addition, synaptic activity controls Al3 generation in vivo (2). Here, we will investigate the dependence of BACE1 axon transport on EHD function and synaptic activity in the hippocampus, a brain region critical for memory formation that is severely affected in AD. We hypothesize that inhibition or stimulation of EHD protein function or synaptic activity will decrease or increase hippocampal BACE1 axon transport, respectively. Our Specific Aims are: 1) Determine whether EHD proteins regulate dynamic BACE1 axon transport in ex vivo hippocampal slice cultures, and 2) Determine whether synaptic activity regulates dynamic BACE1 axon transport in ex vivo hippocampal slice cultures in an EHD-dependent manner. Our studies together with those of Dr. Thinakaran's proposal will increase our understanding of Aj3 production in the brain and may reveal new therapeutic strategies for AD.