Editors' ChoiceAlzheimer’s Disease

Tau-Chopping Enzyme Adds Fuel to the Neurodegeneration Fire

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Science Translational Medicine  12 Nov 2014:
Vol. 6, Issue 262, pp. 262ec196
DOI: 10.1126/scitranslmed.aaa2054

The microtubule-associated protein tau is a bad actor implicated in several age-related neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia. In AD, aggregated species of tau form neurofibrillary tangles in neurons, which are associated with cell death. Mutations in the gene encoding tau cause neurodegeneration in both humans and mice. Despite years of research, the mechanisms mediating tau toxicity in the brain are not well understood, limiting the development of tau-based therapies for AD.

Now, Zhang et al. have identified a new mechanism of tau neurotoxicity, which has clear therapeutic implications. The authors identified a new protease, termed AEP (asparagine endopeptidase), which readily cleaved tau at two sites, generating fragments that were prone to pathological aggregation and were highly toxic to cultured neurons. Deletion of the gene encoding AEP in a mouse model of tau-induced neurodegeneration (the P301S tau transgenic mouse) limited the accumulation of pathogenic tau in the brain and prevented synapse damage and learning deficits. Whereas virus-mediated overexpression of a disease-linked form of tau in mouse brain caused tau pathology and synapse loss, expressing the same tau protein that had been rendered resistant to AEP-mediated cleavage led to less pathology and milder behavioral deficits. AEP protein and proteolytic activity, as well as AEP-specific tau fragments, also increased in the brain in an age-dependent manner in P301S tau transgenic mice. Last, the AD-related amyloid-β peptide (Aβ) induced AEP expression and tau cleavage in mouse neurons, whereas increased AEP protein, proteolytic activity, and tau fragments were observed in post-mortem brain tissue from human AD patients.

These findings suggest that AEP-mediated tau cleavage could play a role in AD pathogenesis. Scientifically, AEP provides a potential link by which Aβ might trigger tau pathology, a pathological event that is thought to be critical in AD but has remained elusive. Clinically, quantification of AEP activity or specific AEP-derived tau fragments might also provide unique diagnostic biomarkers for AD. Last, drugs that inhibit AEP activity may have the potential to exert protective effects in AD patients. Although these findings need to be confirmed in other preclinical models and examined more thoroughly in humans, this study suggests that blocking this tau-chopping enzyme may hold promise as a new therapeutic avenue for AD treatment.

Z. Zhang et al., Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 10.1038/nm.3700 (2014). [Full Text]

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