Enhancement of BACE1 Activity by p25/Cdk5-Mediated Phosphorylation in Alzheimer's Disease

PloS One
Woo-Joo SongSul-Hee Chung

Abstract

The activity of beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is elevated during aging and in sporadic Alzheimer's disease (AD), but the underlying mechanisms of this change are not well understood. p25/Cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathogenesis of several neurodegenerative diseases, including AD. Here, we describe a potential mechanism by which BACE activity is increased in AD brains. First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. Then, we demonstrate that the level of phospho-BACE1 is increased in the brains of AD patients and in mammalian cells and transgenic mice that overexpress p25. Furthermore, the fraction of p25 prepared from iodixanol gradient centrifugation was unexpectedly protected by protease digestion, suggesting that p25/Cdk5-mediated BACE1 phosphorylation may occur in the lumen. These results reveal a link between p25 and BACE1 in AD brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation.

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Citations

Apr 6, 2016·Neuroscience and Biobehavioral Reviews·Riqiang YanRobert Vassar
Apr 18, 2016·Brain Research Bulletin·Wataru Araki
Nov 1, 2016·Personalized Medicine·Patricia Regina ManzineMárcia Regina Cominetti
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Dec 11, 2019·Current Alzheimer Research·Tao-Tao LuZhiyou Cai
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Jun 28, 2016·Experimental and Therapeutic Medicine·Lunxu LiXiangyang Guo
Jan 2, 2020·International Journal of Molecular Sciences·Tao ZhangTae Ho Lee
May 5, 2017·Frontiers in Molecular Neuroscience·Riqiang Yan
Jun 8, 2018·Frontiers in Neuroinformatics·Javaria AshrafZaheer Ul-Haq
Feb 15, 2018·Frontiers in Aging Neuroscience·Md Sahab UddinAdrian M Stankiewicz
May 22, 2021·Frontiers in Cellular Neuroscience·Bradley J BaranowskiRebecca E K MacPherson
Jul 6, 2021·Frontiers in Neuroscience·Ann M SaundersWilliam Kirby Gottschalk

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
BACE
ELISA
enzyme-linked immunosorbent assay
transfection
transgenic
Co-immunoprecipitation

Software Mentioned

Softmax PRO

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