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

Neuron. 2016 Apr 20;90(2):245-60. doi: 10.1016/j.neuron.2016.03.005. Epub 2016 Mar 31.


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.

MeSH terms

  • Acetylation
  • Actins / metabolism*
  • Alzheimer Disease / metabolism
  • Animals
  • Brain / metabolism*
  • Carrier Proteins / metabolism*
  • Hippocampus / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology
  • Memory Disorders / genetics
  • Memory Disorders / physiopathology*
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity / physiology*
  • Phosphoproteins
  • Primary Cell Culture
  • Receptors, AMPA / metabolism*
  • Signal Transduction*
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Actins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Receptors, AMPA
  • Wwc1 protein, mouse
  • tau Proteins