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.
Highlights
The age-dependent deposition of amyloid-b peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark of Alzheimer’s disease (AD)
To investigate whether APP is a substrate of asparagine endopeptidase (AEP), we prepared kidney lysates derived from wild-type (WT; þ / þ ) or AEP knockout ( À / À ) mice at different pH to inactivate or activate AEP, respectively, and incubated with recombinant green fluorescent protein (GFP)-APP
Mutation of either of two key residues in AEP blunted its proteolytic activity against APP (Fig. 1c), including C189 that is essential for the cysteine proteinase activity and N323 that plays a critical role in the cleavage and maturation of AEP17,19
Summary
The age-dependent deposition of amyloid-b peptides, derived from amyloid precursor protein (APP), is a neuropathological hallmark of Alzheimer’s disease (AD). An alternative pathway of anti-amyloidogenic processing of APP occurs within the Ab domain between residues K612 and L613 in APP11,12 and results in the secretion of the large APP aminoterminal domain and the generation of a-CTF (C83). This cleavage is performed by a-secretases, which in neurons includes ADAM10 AEP increases with ageing and proteolytically cleaves APP in the ectodomain, affecting the rate of BACE1 cleavage of the resultant substrate. Blockade of APP cleavage by AEP prevents pathological and behavioural defects induced by overexpression of APP These findings suggest that AEP is activated during ageing and promotes Ab production, contributing to AD onset and progression. AEP may act as a novel d-secretase that mediates APP fragmentation and amyloidogenesis
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