KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
ABSTRACT 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 define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores 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 find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
Wong Ivy、Cifuentes Helen、Le David、Spina Salvatore、Grinberg Lea T.、Seeley William W.、Kramer Joel H.、Sacktor Todd C.、Gan Li、Chen Jackson H.、Casaletto Kaitlin B.、Tracy Tara E.、Nana Alissa L.、Shah Samah、Schilling Birgit、Kauwe Grant、Yao Lei、Li Yaqiao、Pareja-Navarro Kristeen A.、Saloner Rowan
Buck Institute for Research on AgingBuck Institute for Research on AgingGladstone InstitutesMemory and Aging Center, Department of Neurology, University of CaliforniaMemory and Aging Center, Department of Neurology, University of California||Weill Institute for Neurosciences, Department of Pathology, University of CaliforniaMemory and Aging Center, Department of Neurology, University of California||Weill Institute for Neurosciences, Department of Pathology, University of CaliforniaMemory and Aging Center, Department of Neurology, University of CaliforniaThe Robert F. Furchgott Center of Neural and Behavioral Science, Departments of Physiology and Pharmacology, Anesthesiology, and Neurology, State University of New York Health Sciences UniversityHelen and Robert Appel Alzheimer Disease Research Institute, Brain and Mind Research Institute, Weill Cornell MedicineBuck Institute for Research on AgingMemory and Aging Center, Department of Neurology, University of CaliforniaBuck Institute for Research on AgingMemory and Aging Center, Department of Neurology, University of CaliforniaBuck Institute for Research on AgingBuck Institute for Research on AgingBuck Institute for Research on AgingBuck Institute for Research on AgingGladstone InstitutesBuck Institute for Research on AgingMemory and Aging Center, Department of Neurology, University of California
神经病学、精神病学基础医学分子生物学
Wong Ivy,Cifuentes Helen,Le David,Spina Salvatore,Grinberg Lea T.,Seeley William W.,Kramer Joel H.,Sacktor Todd C.,Gan Li,Chen Jackson H.,Casaletto Kaitlin B.,Tracy Tara E.,Nana Alissa L.,Shah Samah,Schilling Birgit,Kauwe Grant,Yao Lei,Li Yaqiao,Pareja-Navarro Kristeen A.,Saloner Rowan.KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2023.06.12.543777.点此复制
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