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

• Published in: The Journal of clinical investigation Vol. 134; no. 3; pp. 1 - 18
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-02-2024
• Subjects: Advertising executives; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Biomarkers; Brain; Brain - metabolism; C-Terminus; Care and treatment; Causes of; Cerebrospinal fluid; Cognition & reasoning; Cognitive ability; Complications and side effects; Development and progression; Disease Models, Animal; Genetic engineering; Health aspects; Humans; Immunological memory; Kidney - metabolism; Kinases; Memory; Memory Disorders - genetics; Memory Disorders - metabolism; Memory, Disorders of; Mice; Mice, Transgenic; Neurodegenerative diseases; Neuronal Plasticity; Neurons; Neuroplasticity; Pathology; Physiological aspects; Protein kinases; Recombinant proteins; Resilience, Psychological; Synaptic plasticity; Tau protein; Tau proteins; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - genetics; Tauopathies - metabolism; Tauopathies - pathology; Transgenic mice; Canada; California; United States; Neuroscience; Alzheimer disease; Memory; Synapses
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI169064

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.