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

Kauwe, G.; Pareja-Navarro, K.; Yao, L.; Chen, J.; Wong, I.; Saloner, R.; Cifuentes, H.; Nana, A. L.; Shah, S.; Li, Y.; Le, D.; Spina, S.; Grinberg, L. T.; Seeley, W. W.; Kramer, J.; Sacktor, T.; Schilling, B.; Gan, L.; Casaletto, K. B.; Tracy, T. E.

doi:10.1101/2023.06.12.543777

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bioRxiv · 10.1101/2023.06.12.543777

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 Alzheimers disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores 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 find that CT-KIBRA binds to and stabilizes protein kinase M{zeta} (PKM{zeta}) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

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Kauwe, G., Pareja-Navarro, K., Yao, L., Chen, J., Wong, I., Saloner, R., Cifuentes, H., Nana, A. L., Shah, S., Li, Y., Le, D., Spina, S., Grinberg, L. T., Seeley, W. W., Kramer, J., Sacktor, T., Schilling, B., Gan, L., Casaletto, K. B., Tracy, T. E.. 2023-06-13. KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss. https://doi.org/10.1101/2023.06.12.543777

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