Summary

This proposal investigates BACE1, one of the enzymes critical for the production of Alzheimer's disease amyloid beta production. We are interested in deciphering the molecular principles of BACE1 trafficking in lipid rafts and non-raft domains using biochemical and live cell imaging approaches in order to elucidate the cell biology of BACE1 processing of amyloid precursor protein (APP). Our studies will uncover novel and significant basic insights into cellular processes that modulate amyloid beta production, thus contributing to the development of strategies aimed at reducing amyloid beta burden.

Project Details

Introduction
Alzheimer's disease (AD) is the major cause of dementia in the elderly. Toxic amyloid beta peptides accumulate in the brains of individuals with AD. Production and accumulation of amyloid beta are central events in AD pathogenesis.

Hypothesis and Specific Aims
Our proposal seeks to investigate the regulation of amyloid beta production. Sequential cell division of amyloid precursor protein (APP) by BACE1 and gamma secretase generates amyloid beta peptides. Our investigation focuses on BACE1. We seek to investigate membrane localization and movement of BACE1 in cultured cells and hippocampal neurons. Our first aim is to characterize BACE1 association with specialized cholesterol-rich microdomains of cellular membranes, called lipid rafts, which play important roles in amyloid beta production. Our second aim is to explore the dynamics of BACE1 movement through the cells using live cell imaging strategies.

Long-term Goals
A better understanding of localization and dynamics of BACE1 movement in cells will shed more light on the mechanisms involved in amyloid beta production. Information stemming from our biochemical, molecular and cellular investigations will contribute to the development of novel and rational strategies for therapeutic intervention for AD aimed at reducing amyloid beta burden.