Molecular Basis of Cell and Developmental Biology
PAR-4 Is Involved in Regulation of β-Secretase Cleavage of the Alzheimer Amyloid Precursor Protein*

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Mounting evidence indicates that aberrant production and aggregation of amyloid β-peptide (Aβ)-(1–42) play a central role in the pathogenesis of Alzheimer disease (AD). Aβ is produced when amyloid precursor protein (APP) is cleaved by β- and γ-secretases at the N and C termini of the Aβ domain, respectively. The β-secretase is membrane-bound aspartyl protease, most commonly known as BACE1. Because BACE1 cleaves APP at the N terminus of the Aβ domain, it catalyzes the first step in Aβ generation. PAR-4 (prostate apoptosis response-4) is a leucine zipper protein that was initially identified to be associated with neuronal degeneration and aberrant Aβ production in models of AD. We now report that the C-terminal domain of PAR-4 is necessary for forming a complex with the cytosolic tail of BACE1 in co-immunoprecipitation assays and in vitro pull-down experiments. Overexpression of PAR-4 significantly increased, whereas silencing of PAR-4 expression by RNA interference significantly decreased, β-secretase cleavage of APP. These results suggest that PAR-4 may be directly involved in regulating the APP cleavage activity of BACE1. Because the increased BACE1 activity observed in AD patients does not seem to arise from genetic mutations or polymorphisms in BACE1, the identification of PAR-4 as an endogenous regulator of BACE1 activity may have significant implications for developing novel therapeutic strategies for AD.

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This work was supported by NINDS Grant R01 NS043296 from the National Institutes of Health, the Alzheimer Association, the Amyotrophic Lateral Sclerosis Association, and the American Federation for Aging Research (to Q. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.