title: Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Tracy
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 91458, USA.
authors.forename: Peter Dongmin
authors.initials: PD
authors.lastname: Sohn
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA.
authors.forename: S Sakura
authors.initials: SS
authors.lastname: Minami
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Min
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA.
authors.forename: Yaqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA.
authors.forename: David
authors.initials: D
authors.lastname: Le
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Lo
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Ponnusamy
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cong
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 91458, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 91458, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 91458, USA. Electronic address: lgan@gladstone.ucsf.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000107:Acetylation; D000199:Actins / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D010750:Phosphoproteins; D061251:Primary Cell Culture; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D018091:Receptors, AMPA; C539495:Wwc1 protein, mouse; D016875:tau Proteins