Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

Carli K. Opland; Miles R. Bryan; Braxton Harris; Jake McGillion-Moore; Xu Tian; Youjun Chen; Michelle S. Itano; Graham H. Diering; Rick B. Meeker; Todd J. Cohen

iScience (Jun 2023)

Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

Carli K. Opland,
Miles R. Bryan,
Braxton Harris,
Jake McGillion-Moore,
Xu Tian,
Youjun Chen,
Michelle S. Itano,
Graham H. Diering,
Rick B. Meeker,
Todd J. Cohen

Affiliations

Carli K. Opland: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Miles R. Bryan: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Braxton Harris: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Jake McGillion-Moore: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Xu Tian: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Youjun Chen: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Michelle S. Itano: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA
Graham H. Diering: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA
Rick B. Meeker: Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Todd J. Cohen: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA; Corresponding author

Journal volume & issue: Vol. 26, no. 6
p. 106905

Abstract

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Summary: Tau-mediated toxicity is associated with cognitive decline and Alzheimer’s disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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