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KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

ABSTRACT: The dynamic function of synapses is critical for encoding memories in the brain. Pathogenic tau obstructs glutamatergic synapse function by blocking long-term potentiation (LTP), representing a key mechanism underlying memory impairment in Alzheimer s disease (AD). Here we developed a strategy for KIdney/BRAin (KIBRA)-mediated LTP repair in neurons with pathogenic tau using the C-terminus of KIBRA (CT-KIBRA). We show that CT-KIBRA restores LTP and memory in transgenic mice expressing human tau that mimics pathogenic hyperacetylated tau found in AD and other tauopathies. CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss in the transgenic mouse brain, instead, we show that CT-KIBRA binds to and stabilizes protein kinase M zeta (PKM zeta) to maintain plasticity and memory despite tau pathogenesis. Further, in humans we established that KIBRA levels in brain and cerebrospinal fluid correlate with tau and cognitive impairment in tauopathies. Our study provides evidence to support KIBRA as a tauopathy-related synaptic biomarker and a synapse repair therapeutic to ameliorate cognitive impairment.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling

PROVIDER: MSV000090510 | MassIVE | Tue Oct 11 11:29:00 BST 2022

SECONDARY ACCESSION(S): PXD037299

REPOSITORIES: MassIVE

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KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

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