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

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 KIBR...

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Vydáno v:	The Journal of clinical investigation Ročník 134; číslo 3; s. 1 - 18
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Clinical Investigation 01.02.2024
Témata:	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 Neuroscience Pathology Physiological aspects Protein kinases Recombinant proteins Resilience, Psychological Synapses 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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI169064