1. KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
- Author
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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, and Tracy, Tara E
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Acquired Cognitive Impairment ,Brain Disorders ,Frontotemporal Dementia (FTD) ,Dementia ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Neurosciences ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Neurological ,Mice ,Animals ,Humans ,tau Proteins ,Resilience ,Psychological ,Tauopathies ,Brain ,Alzheimer Disease ,Memory Disorders ,Neuronal Plasticity ,Mice ,Transgenic ,Kidney ,Disease Models ,Animal ,Alzheimer disease ,Memory ,Neuroscience ,Synapses ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - 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 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.
- Published
- 2024