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

  • Kauwe, Grant
  • Pareja-Navarro, Kristeen A
  • Yao, Lei
  • Chen, Jackson H
  • Wong, Ivy
  • Saloner, Rowan
  • Cifuentes, Helen
  • Nana, Alissa L
  • Shah, Samah
  • Li, Yaqiao
  • Le, David
  • Spina, Salvatore
  • Grinberg, Lea T
  • Seeley, William W
  • Kramer, Joel H
  • Sacktor, Todd C
  • Schilling, Birgit
  • Gan, Li
  • Casaletto, Kaitlin B
  • Tracy, Tara E
Publication Date
Feb 01, 2024
eScholarship - University of California
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Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

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