Microdomain Localization And Trafficking Of BACE1
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.
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.
In a second line of investigation, the team used live cell imaging and high-speed video microscopy analysis to study how BACE1 is transported within cultured cell lines and in cultured hippocampal nerve cells. Their studies show that BACE1 is largely localized in membrane organelles involved in the recycling of cell surface proteins. By specifically labeling the BACE1 protein that was exposed to the cell surface, they were able to follow the movement of BACE1 inside neurons in real time. These studies have provided novel insights into neuronal trafficking of BACE1, and have identified novel regulators involved in axonal transport of BACE1. Dr. Thinakaran’s future studies will determine the significance and effect of the BACE1 axonal transport on APP processing and beta-amyloid production in nerve cells.
Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and Proteolytic Processing of APP. Cold Spring Harb Perspect Med. 2012 May;2(5):a006270. [PMID: 22553493]
Parent AT, Thinakaran G. (2010) Modeling presenilin-dependent familial Alzheimer's disease: emphasis on presenilin substrate-mediated signaling and synaptic function. Int J Alzheimers Dis. 2010:825918.
Vetrivel KS, Thinakaran G. (2010) Membrane rafts in Alzheimer's disease beta amyloid production. Biochim Biophys Acta. 2010 Aug;1801(8):860-7
First published on: April 14, 2009
Last modified on: April 4, 2012