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Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease

Abstract

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 human AD brain and tau P301S–transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S–transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.

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Figure 1: AEP cleaves tau in vitro.
Figure 2: AEP cleaves tau at N255 and N368.
Figure 3: AEP is upregulated and cleaves tau during aging and in AD.
Figure 4: Tau cleavage by AEP disrupts its MT assembly activity and is toxic to neurons.
Figure 5: Lgmn deficiency prevents tau phosphorylation, synaptic dysfunction and memory deficits in tau P301S–transgenic mice.
Figure 6: Blocking of tau cleavage by AEP prevents tau P301S–induced synaptic dysfunction and cognitive impairment.

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Acknowledgements

This work was supported by RO1grants (NS045627 and NS060680) from the US National Institutes of Health to K.Y., the US National Institutes of Health/National Institute on Aging Alzheimer's Disease Research Centers (P50AG025688) grant to A.I.L., a grant from the National Natural Science Foundation of China (no. 81100958) to Z.Z., a grant from the National Natural Science Foundation of China (no. 91132305) to J.Z.W., a National Key Basic Research Program of China grant (2010CB945202) to Y.E.S. and a National Science Foundation of China grant (81330030) to L.C. and Y.E.S. We thank D. Weinshenker (Emory University) for tau P301S–transgenic mice, M. Asano (Kanazawa University) for Lgmn knockout mice, S. Kuegler (Max Planck Institute of Psychiatry) for pAAV vectors carrying tau GFP and C. Hales (Emory University) for technical support.

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K.Y. conceived the project, designed the experiments and wrote the manuscript. Z.Z. designed and performed most of the experiments. M.S. and S.P.Y. performed the electrophysiological experiments. X.L. prepared primary neurons and assisted with animal experiments. S.S.K. performed the stereotaxic injection of virus. D.M.D. and N.T.S. performed the mass spectrometry analysis. I.-S.K. assisted with the molecular biology experiments. L.C., W.T.H., Z.L., J.Z.-W., Y.E.S. and A.I.L. designed the experiments, assisted with data analysis and interpretation and critically read the manuscript.

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Correspondence to Liming Cheng or Keqiang Ye.

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Zhang, Z., Song, M., Liu, X. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat Med 20, 1254–1262 (2014). https://doi.org/10.1038/nm.3700

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