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

doi:10.1016/j.isci.2023.106905

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

iScience. 2023 May 19;26(6):106905. doi: 10.1016/j.isci.2023.106905. eCollection 2023 Jun 16.

Authors

Carli K Opland^{1

2}, Miles R Bryan^{1

2}, Braxton Harris², Jake McGillion-Moore^{1

2}, Xu Tian^{1

2}, Youjun Chen^{1

2}, Michelle S Itano^{1

3}, Graham H Diering^{1

3}, Rick B Meeker², Todd J Cohen^{1

2

3

4}

Affiliations

¹ UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA.

Abstract

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.

Keywords: Cellular neuroscience; Molecular neuroscience.