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Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.

TitleAcetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.
Publication TypeJournal Article
Year of Publication2016
AuthorsTracy TE, Sohn PDongmin, S Minami S, Wang C, Min S-W, Li Y, Zhou Y, Le D, Lo I, Ponnusamy R, Cong X, Schilling B, Ellerby LM, Huganir RL, Gan L
JournalNeuron
Volume90
Issue2
Pagination245-60
Date Published2016 04 20
ISSN1097-4199
KeywordsAcetylation, Actins, Alzheimer Disease, Animals, Brain, Carrier Proteins, Hippocampus, Humans, Long-Term Potentiation, Memory Disorders, Mice, Mice, Transgenic, Neuronal Plasticity, Primary Cell Culture, Receptors, AMPA, Signal Transduction, tau Proteins
Abstract

Tau toxicity has been implicated in the emergence of synaptic dysfunction in Alzheimer's disease (AD), but the mechanism by which tau alters synapse physiology and leads to cognitive decline is unclear. Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein. Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA. These findings suggest a novel mechanism by which pathogenic tau causes synaptic dysfunction and cognitive decline in AD pathogenesis.

DOI10.1016/j.neuron.2016.03.005
Alternate JournalNeuron
PubMed ID27041503
PubMed Central IDPMC4859346
Grant ListF32 AG043301 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
RL1 NS062413 / NS / NINDS NIH HHS / United States
R01 NS036715 / NS / NINDS NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
R01 NS040251 / NS / NINDS NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States