The physical approximation of APP and BACE-1: A key event in alzheimer's disease pathogenesis

Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid (A) in brains. A is derived by sequential cleavage of the amyloid precursor protein (APP) by -site secretase enzyme (BACE-1) and -secretase. Proteolytic processing of APP by BACE-1 is the rate-limiting step in A production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway. Here, we highlight recent research on intracellular trafficking/sorting of APP and BACE-1, and discuss how dysregulation of these pathways might lead to enhanced convergence of APP and BACE-1, and subsequent -cleavage of APP. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 340-347, 2018