Keeping the balance of amyloid β with proteases on both sides of the equation

CASTAÑO EM; SURACE EI; LEAL M.C; MORELLI L

Puerto Madryn

Congreso; XLVI Reunión Anual de la SAIB; 2010

SAIB

The progressive accumulation of amyloid b peptides (Abs), a major feature of the aged human brain, is deeply exacerbated in Alzheimer's disease (AD), Down syndrome (DS) and hereditarydementias. Regardless of the role of Abs in the pathogenesis of these diseases, the mechanisms leading to their accumulation are poorly understood. Abs are released by sequential endoproteolysis of a transmembrane amyloid precursor protein (APP). The aspartyl proteases BACE1 and g-secretase generate the amino and carboxyl-termini of Ab peptides, respectively. Within endogenous levels of APP, the activity of BACE1 determines the rate of Abs generation. After being released, Abs is purportedly removed by transport to the circulation and in situ proteolysis by Zn2+ metallopeptidases such as insulin-degrading enzyme (IDE) and neprilysin (NEP), among others. In sporadic AD, BACE1expression and activity are increased while IDE and NEP activities are reduced, consistent with an unbalanced process leading to higher steady-state levels of Abs. We have recently identified possible subcellular sites of Abs-IDE interactions and a likely mechanism for IDE non-classical secretion implicated in degradation of extracellular Abs. Understanding how BACE1 and IDE activities are modulated may provide additional insight into Abs homeostasis regulation in health and disease.