title: Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits.
abstract: Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Min
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Tracy
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Yaqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S Sakura
authors.initials: SS
authors.lastname: Minami
authors.affiliation: Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Erwin
authors.initials: E
authors.lastname: Defensor
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sue Ann
authors.initials: SA
authors.lastname: Mok
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Peter Dongmin
authors.initials: PD
authors.lastname: Sohn
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cong
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ellerby
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Bradford W
authors.initials: BW
authors.lastname: Gibson
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
authors.forename: Nevan
authors.initials: N
authors.lastname: Krogan
authors.affiliation: Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gestwicki
authors.affiliation: Department of Neuroscience, University of California, San Diego, San Diego, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California, USA.|Department of Neurology, University of California, San Francisco, San Francisco, California, USA.|Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D016875:tau Proteins