PALMITATE INDUCES BACE1 EXPRESSION AND ACTIVITY BY INDUCING STEROL RESPONSE ELEMENT BINDING PROTEIN 1 EXPRESSION AND ACTIVATION IN THE MOUSE HIPPOCAMPUS AND HUMAN SH-SY5Y NEUROBLASTOMA CELLS

Abstract

The etiology of Alzheimer's disease (AD) is multifactorial and poorly defined and characterized by a dynamic interplay of a myriad of risk variables that include dietary and environmental factors. Epidemiological studies have implicated saturated fat-enriched diets in the etio-pathogenesis of AD. The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) catalyzes the rate limiting step in amyloid-beta (Aβ) production, a peptide that serves as a core instigator of pathophysiological neurodegenrative processes in AD. Emerging evidence from our laboratory studies and other contemporary studies have shown that saturated fat-enriched diets, such as palmitate-enriched diets, increase BACE1 activity and enhance Aβ production. Our preliminary studies have shown that a palmitate-enriched diet increases the expression and activity of Sterol Response Element binding protein 1 (SREBP1) in the mouse hippocampus. In this study, we determined the role of SREBP1 activation in the palmitate-induced increase in BACE1 expression, activity, and subsequent Aβ genesis. We fed nine-month old C57BL/6J mice a palmitate-enriched diet or the respective control-chow diet for three months and determined the extent to which increased SREBP1 expression and activity plays a role in the palmitate-enriched diet-induced increase in BACE1 expression, activity, and Aβ genesis in the hippocampus. We also determined the role SREBP1 activation in the induction of BACE1 expression, activity, and Aβ genesis in exogenous palmitate-treated human SH-SY5Y neuroblastoma cells and delineated the underlying mechanisms involved. Our ChIP analysis and luciferase reporter assays show that palmitate-induced SREBP1 activation directly regulates BACE1 expression at the transcriptional level. Knocking-down or ectopic expression of the dominant negative SREBP1 mutant significantly mitigated the palmitate-induced BACE1 expression and subsequent Aβ genesis. Our study elucidates a novel signaling pathway and SREBP1 as a unique downstream effector of palmitate-induced up-regulation in BACE1 expression and subsequent Aβ genesis.