title: Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice.
abstract: A152T-variant human tau (hTau-A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau-A152T or wild-type hTau (hTau-WT), we find age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau-A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau-A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau-A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau-A152T and amyloid-β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Biljana
authors.initials: B
authors.lastname: Djukic
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Taneja
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Lo
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Davis
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Craft
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Weikun
authors.initials: W
authors.lastname: Guo
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Ponnusamy
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
authors.forename: T Michael
authors.initials: TM
authors.lastname: Gill
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA, USA Department of Neurology, University of California, San Francisco, San Francisco, CA, USA lennart.mucke@gladstone.ucsf.edu.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000503:physiopathology; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D024801:Tauopathies / Q000235:genetics / Q000503:physiopathology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins
keywords: A152T; Alzheimer's disease; frontotemporal dementia; hyperexcitability; tau