Dysregulated Metabolism of the Amyloid-ß Protein and Therapeutic Approaches in Alzheimer Disease.

ABSTRACT

Amyloid-ß protein (Aß) is the main component of senile plaques in the brains of Alzheimer disease (AD) patients. Aß is proteolytically derived from amyloid-ß precursor protein by ß- and γ-secretases. Secreted Aß is then eliminated from the central nervous system by multiple clearance mechanisms, including phagocytosis, immune responses, and proteolytic degradation. These dynamic metabolic processes, which are referred to as Aß economy, regulate steady-state brain Aß levels. Familial AD-linked genetic mutations augment the production and aggregation of Aß. In contrast, rare genetic variants that reduce Aß production were protective against AD. Moreover, decreased Aß clearance has been demonstrated in sporadic AD patients, suggesting that dysregulation of Aß economy contributes to the development of AD. Thus, several approaches to inhibit the production as well as to enhance the clearance of Aß have been investigated as potential therapeutics against AD. In this manuscript, we introduce the molecules and cellular mechanisms involved in the regulation of Aß economy and discuss the current understanding of these processes in the development of therapeutics against AD. J. Cell. Biochem. 118 4183-4190, 2017. © 2017 Wiley Periodicals, Inc.