title: Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease.
abstract: Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To better understand the role of tau-mediated effects on pathophysiology and global central nervous system function, we extensively characterized gene expression, pathology and behavior of the rTg4510 mouse model, which overexpresses a mutant form of human tau that causes Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We found that the most predominantly altered gene expression pathways in rTg4510 mice were in inflammatory processes. These results closely matched the causal immune function and microglial gene-regulatory network recently identified in AD. We identified additional gene expression changes by laser microdissecting specific regions of the hippocampus, which highlighted alterations in neuronal network activity. Expression of inflammatory genes and markers of neuronal activity changed as a function of age in rTg4510 mice and coincided with behavioral deficits. Inflammatory changes were tau-dependent, as they were reversed by suppression of the tau transgene. Our results suggest that the alterations in microglial phenotypes that appear to contribute to the pathogenesis of Alzheimer's disease may be driven by tau dysfunction, in addition to the direct effects of beta-amyloid.
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Wes
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Corradi
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: DeCarr
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Truong
authors.affiliation: Department of Applied Genomics, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Nestor X
authors.initials: NX
authors.lastname: Barrezueta
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Polson
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Bourin
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Flynn
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Keenan
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Lidge
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Jere
authors.initials: J
authors.lastname: Meredith
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: Natale
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Greg W
authors.initials: GW
authors.lastname: Cadelina
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Charlie F
authors.initials: CF
authors.lastname: Albright
authors.affiliation: Department of Neuroscience, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Cacace
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D017628:Microglia / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
chemical_list: D008869:Microtubule-Associated Proteins; D016875:tau Proteins