Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction

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12 Scopus citations

Abstract

Chronic traumatic encephalopathy (CTE) is associated with repeated traumatic brain injuries (TBI) and is characterized by cognitive decline and the presence of neurofibrillary tangles (NFTs) of the protein tau in patients’ brains. Here we provide direct evidence that cell-scale mechanical deformation can elicit tau abnormalities and synaptic deficits in neurons. Using computational modeling, we find that the early pathological loci of NFTs in CTE brains are regions of high deformation during injury. The mechanical energy associated with high-strain rate deformation alone can induce tau mislocalization to dendritic spines and synaptic deficits in cultured rat hippocampal neurons. These cellular changes are mediated by tau hyperphosphorylation and can be reversed through inhibition of GSK3β and CDK5 or genetic deletion of tau. Together, these findings identify a mechanistic pathway that directly relates mechanical deformation of neurons to tau-mediated synaptic impairments and provide a possibly exploitable therapeutic pathway to combat CTE.

Original languageEnglish (US)
Pages (from-to)29069-29079
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Peter Teravskis for his technical expertise and thoughtful discussions. Funding was provided by NIH Grants R21-NS096437-01 (D.L. and P.W.A.) and R61 NS115089-01 (D.L.), Minnesota Higher Education Grant (D.L. and P.W.A.), Institute of Engineering Medicine

Funding Information:
at the University of Minnesota (UMN) seed grant (P.W.A. and D.L.), UMN– Mayo Partnership Grant (D.L.), and NSF Grants Civil, Mechanical and Manufacturing Innovation (CMMI) 1553255 (P.W.A.) and CMMI 1935834 (P.W.A. and D.L.).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Traumatic brain injuries | dendritic spines | tau | chronic traumatic encephalopathy | synaptic deficits

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