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KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
Grant Kauwe, … , Kaitlin B. Casaletto, Tara E. Tracy
Grant Kauwe, … , Kaitlin B. Casaletto, Tara E. Tracy
Published February 1, 2024
Citation Information: J Clin Invest. 2024;134(3):e169064. https://doi.org/10.1172/JCI169064.
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Research Article Neuroscience

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

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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.

Authors

Grant Kauwe, Kristeen A. Pareja-Navarro, Lei Yao, Jackson H. Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L. Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Joel H. Kramer, Todd C. Sacktor, Birgit Schilling, Li Gan, Kaitlin B. Casaletto, Tara E. Tracy

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Figure 3

CT-KIBRA expression in hippocampus reverses memory impairment in tauKQhigh mice.

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CT-KIBRA expression in hippocampus reverses memory impairment in tauKQhi...
(A and B) The object-context discrimination test was used to assess pattern separation memory (n = 10–12 mice/group). (A) During the sample phase, the mean proportion of time that mice spent exploring 2 identical objects in each context was calculated (X1 and X2 in Context 1, or Y1 and Y2 in Context 2). (B) Mean percent time spent exploring the incongruent and congruent objects in both contexts for each group was analyzed during the test phase of the object-context discrimination test (*P < 0.05, paired Student’s t test). (C) Graphs of the mean percentage of spontaneous alternations completed by the mice in the Y-maze within 5 minutes (left) and the average number of total Y-maze arm entries made by the mice (right) (n = 11–13 mice/group; *P < 0.05, 1-way ANOVA, Bonferonni post hoc analyses). (D–F) Mice were tested for spatial learning and memory in the MWM (n = 11–13 mice/group). (D) The mean distance traveled to the hidden platform and the average swim velocity were measured during hidden platform training (P > 0.05, repeated measures 2-way ANOVA). (E) Representative swim paths of mice during the probe trials for spatial memory testing performed at 24 hours and 7 days after hidden platform training. (F) Graphs of the mean percent time spent in the target quadrant compared with the average time spent in the other quadrants in the 24 hour (left) and 7-day (right) probe trials. Comparisons between target quadrant and other quadrants were analyzed for both the first 20 second and the total 60 second period of the probe trial for all mice (*P < 0.05, **P < 0.01, and ***P < 0.001, paired Student’s t test). The dotted line marks the 25% chance level. Values are given as means ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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