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Caspase-2 cleavage of tau reversibly impairs memory

Abstract

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

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Figure 1: Levels of the tau cleavage product TCP35 correlate with memory deficits.
Figure 2: Caspase-2 cleaves tau and generates Δtau314.
Figure 3: Reducing caspase-2 levels restores memory function.
Figure 4: Effects of cleavage at Asp314 on tau mislocalization to dendritic spines, synaptic transmission and glutamate receptor localization.
Figure 5: Mutating Asp314 to Glu314 prevents tauP301L from causing cognitive deficits and neurodegeneration.
Figure 6: Missorting of Δtau314 to dendritic spines is not sufficient to disrupt synaptic or memory function.

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Acknowledgements

Sources of funding for this study include the US National Institutes of Health (NIH) (EUREKA grant no. R01-NS63214 (K.H.A.) and R01-NS79374 (K.H.A.)), the T. and P. Grossman Family Foundation (K.H.A.), B. Grossman (K.H.A.) and K. Moe (K.H.A.). We thank P. Davies (Albert Einstein College of Medicine) for the antibodies Alz-50, MC-1 and CP-13, as well as B. Roth (University of North Carolina at Chapel Hill) for the pAAV-CaMKIIa-EGFP vector. We are grateful to the participants of the Memory and Aging Project, as well as the staff and director (D. Bennett) of the Rush Alzheimer's Disease Center (grant no. R01-AG17917 (D. Bennett)). We thank L. Kemper, K. Leinonen and E. Steuer for excellent assistance with mouse breeding, genotyping and behavioral tests, M. Kuskowski for help with statistical analyses, and C. Wilmot, D. Liao, M. Koob and M. Walters for valuable advice and encouragement.

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K.H.A. conceived and supervised the project, designed the experiments and wrote the manuscript; X.Z. designed and performed the experiments and wrote the manuscript; L.A.K. designed and performed the behavioral experiments; B.S. performed the electrophysiological experiments and prepared the postsynaptic fractions; C.H. performed the behavioral experiments; K.Z. performed hippocampal volume quantification; M.R. contributed to the initial identification of Δtau314; and J.C. contributed to the behavioral experiments.

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Correspondence to Karen H Ashe.

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Zhao, X., Kotilinek, L., Smith, B. et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med 22, 1268–1276 (2016). https://doi.org/10.1038/nm.4199

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