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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Veröffentlicht in:The Journal of clinical investigation Jg. 134; H. 3; S. 1 - 18
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.02.2024
Schlagworte:
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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
Online-Zugang:Volltext
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI169064