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.
Highlights
Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that is characterized by dementia
A band corresponding to the molecular size of BACE1 was detected by autoradiography only when both BACE1 and p25/Cyclin-dependent kinase 5 (Cdk5) were present in the reaction mixture (Fig 1A)
An examination of the amino acid sequence of BACE1 revealed the presence of a consensus Cdk5 phosphorylation site at Thr252, which was followed by proline and basic amino acids that are conserved in humans, rats, and mice (Fig 1B)
Summary
Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that is characterized by dementia. The brains of AD patients have pathological hallmarks, including amyloid plaques and neurofibrillary tangles, insoluble deposits made of proteins called Aβ and hyperphosphorylated tau, respectively. Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), a β-secretase, cleaves APP during an initial step in Aβ generation [1]. Subsequent cleavage by a γ-secretase complex including Presenilin produces Aβ. The importance of Aβ in PLOS ONE | DOI:10.1371/journal.pone.0136950. The importance of Aβ in PLOS ONE | DOI:10.1371/journal.pone.0136950 August 28, 2015
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
