Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. AEP is upregulated and active during aging, and is activated in tau P301S transgenic mice and human AD brain, leading to tau truncation in NFTs. Deletion of AEP from tau P301S transgenic mice substantially reduces tau hyperphosphorylation, alleviates the synapse loss and rescues impaired hippocampal synaptic function and the cognitive deficits. Infection of uncleavable tau N255AN368A mutant rescues tau P301S-induced pathological and behavioral defects. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes in neurodegenerative diseases. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.

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.

Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/ tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Abinduced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Ab deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.