PAR-4 is involved in regulation of beta-secretase cleavage of the Alzheimer amyloid precursor protein.
Mounting evidence indicates that aberrant production and aggregation of amyloid beta-peptide (Abeta)-(1-42) play a central role in the pathogenesis of Alzheimer disease (AD). Abeta is produced when amyloid precursor protein (APP) is cleaved by beta- and gamma-secretases at the N and C termini of the Abeta domain, respectively. The beta-secretase is membrane-bound aspartyl protease, most commonly known as BACE1. Because BACE1 cleaves APP at the N terminus of the Abeta domain, it catalyzes the first step in Abeta generation. PAR-4 (prostate apoptosis response-4) is a leucine zipper protein that was initially identified to be associated with neuronal degeneration and aberrant Abeta 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, beta-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.
Xie
Jun
J
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Guo
Qing
Q
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C101296:prostate apoptosis response-4 protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse