|KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.
|Year of Publication
|Kauwe G, Pareja-Navarro KA, Yao L, Chen JH, Wong I, Saloner R, Cifuentes H, Nana AL, Shah S, Li Y, Le D, Spina S, Grinberg LT, Seeley WW, Kramer JH, Sacktor TC, Schilling B, Gan L, Casaletto KB, Tracy TE
|2023 Jun 12
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 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 Mζ (PKMζ) 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.
|PubMed Central ID
|P50 AG023501 / AG / NIA NIH HHS / United States
R37 MH057068 / MH / NIMH NIH HHS / United States
S10 OD016281 / OD / NIH HHS / United States
K01 AG057862 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R03 AG063248 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
R01 MH057068 / MH / NIMH NIH HHS / United States