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.
View: Text | PDF
Research Article Neuroscience

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

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

×

Figure 6

CT-KIBRA maintains plasticity-related PKMζ levels underlying resilience to tau-mediated synaptic and memory deficits.

Options: View larger image (or click on image) Download as PowerPoint
CT-KIBRA maintains plasticity-related PKMζ levels underlying resilience ...
(A) Representative images of dendritic spines on cultured hippocampal neurons expressing mApple (red) with or without tauKQ and CT-KIBRA. Immunolabeling of endogenous PKMζ (cyan) was monitored in spines on neurons that were unstimulated or subjected to cLTP treatment (arrowheads). Scale bar: 5 μm. (B) Quantification of PKMζ immunoreactivity in postsynaptic spines with or without cLTP induction normalized to postsynaptic PKMζ levels in control unstimulated neurons (n = 12–15 cells/group; *P < 0.05, unpaired Student’s t test). (C) Representative immunoblots of PKMζ, PSD-95, and GAPDH from hippocampal homogenates of 3 individual ntg lenti-control, taukQhigh lenti-control and taukQhigh lenti-CT-KIBRA mice. (D) Quantification of total PKMζ levels in hippocampal homogenates normalized to GAPDH and to PSD-95 (n = 10–13 mice/group; *P < 0.05, **P < 0.01, 1-way ANOVA, Bonferonni post hoc analyses). Values are given as means ± SEM. See also Supplemental Figure 6. (E) Pearson correlation analyses between PKMζ levels relative to GAPDH analyzed from hippocampal homogenates and the percent time each mouse spent exploring the incongruent object in the object-context discrimination test of pattern separation memory (n = 10–12 mice/group). (F) Pearson correlation analyses of the proportion of time each mouse spent in the target quadrant of the MWM during the 7-day probe test and the corresponding PKMζ levels in hippocampus relative to PSD-95 (n = 10–13 mice/group). (G) Pearson correlation analyses of spontaneous alternations made in the Y-maze test and total PKMζ levels in hippocampus (n = 11–13 mice/group).