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

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 n

SUBMITTER: Opland CK 

PROVIDER: S-EPMC10251131 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature