Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26549211.
- Also identified by DOI 10.1038/ncomms9762 and PMC identifier 4659940.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The age-dependent deposition of amyloid-β peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark of Alzheimer's disease (AD). Despite age being the greatest risk factor for AD, the molecular mechanisms linking ageing to APP processing are unknown. Here we show that asparagine endopeptidase (AEP), a pH-controlled cysteine proteinase, is activated during ageing and mediates APP proteolytic processing. AEP cleaves APP at N373 and N585 residues, selectively influencing the amyloidogenic fragmentation of APP. AEP is activated in normal mice in an age-dependent manner, and is strongly activated in 5XFAD transgenic mouse model and human AD brains. Deletion of AEP from 5XFAD or APP/PS1 mice decreases senile plaque formation, ameliorates synapse loss, elevates long-term potentiation and protects memory. Blockade of APP cleavage by AEP in mice alleviates pathological and behavioural deficits. Thus, AEP acts as a δ-secretase, contributing to the age-dependent pathogenic mechanisms in AD.
Medical subject headings
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Brain
- Cysteine Endopeptidases
- Hippocampus