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

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Figure 7

CT-KIBRA restores AMPAR trafficking during LTP by interacting with PKMζ in neurons with pathogenic tau.

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CT-KIBRA restores AMPAR trafficking during LTP by interacting with PKMζ ...
(A) Representative confocal images of surface GluA1 immunostaining (green) in spines of cultured hippocampal neurons expressing mApple (red), tauKQ, and CT-KIBRA. Unstimulated and cLTP neurons were treated with a PKMζ antisense or a scrambled control oligodeoxynucleotide. Scale bar: 2 μm. (B) Quantification of the surface GluA1 immunofluorescence in spines normalized to unstimulated neurons treated with the scrambled oligodeoxynucleotide (n = 13–18 neurons/group; *P < 0.05, unpaired Student’s t test). See also Supplemental Figure 7, A–D. (C) Images of HEK293 cells transfected with GFP (green) and HA-PKMζ together with flag-CT-KIBRA or a flag-CT-KIBRA-AAA mutant carrying R965A, S967A, and R969A mutations. Anti-flag and anti-HA antibodies were used for detection of PLA signal (red) signifying the close proximity of flag-CT-KIBRA and HA-PKMζ in the HEK293 cells. Scale bar: 10 μm. (D) Quantification of the mean PLA fluorescence intensity detected in HEK293 cells transfected with HA-PKMζ alone (control), or cotransfected with flag-CT-KIBRA constructs (n = 27–30 cells/group; ***P < 0.001, 1-way ANOVA, Bonferonni post hoc analyses). (E) Representative confocal images of dendrites and spines on neurons cotransfected with mApple (red) and tauKQ with CT-KIBRA or CT-KIBRA-AAA. Scale bar: 2 μm. (F) Quantification of surface GluA1 immunofluorescence in spines of tauKQ-expressing neurons showing that cLTP-induced postsynaptic receptor insertion is reestablished by CT-KIBRA, but not CT-KIBRA-AAA. GluA1 levels were normalized to the intensity of staining in spines of unstimulated tauKQ neurons (n = 14 neurons/group; *P < 0.05, unpaired Student’s t test). Values are given as means ± SEM. See also Supplemental Figure 7, E and F. (G) Model depicting the impact of KIBRA and PKMζ on postsynaptic AMPAR trafficking during NMDA receptor–dependent (NMDAR-dependent) LTP in healthy conditions (left) and in tauopathy (middle). Expression of CT-KIBRA in tauopathy neurons (right) with high pathogenic acetylated tau levels can restore postsynaptic AMPAR recruitment during plasticity, which mechanistically involves the interaction between CT-KIBRA and PKMζ.