title: Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.
abstract: Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.
authors.affiliation: Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.|Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Illsung L
authors.initials: IL
authors.lastname: Joo
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Lai
authors.affiliation: Fundamental Neurobiology, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, Ontario, M5T 2R1, Canada.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bazzigaluppi
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Koletar
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Dorr
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Lynsie A M
authors.initials: LA
authors.lastname: Thomason
authors.affiliation: Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.|Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.affiliation: Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A1, Canada.
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
authors.affiliation: Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.|Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Stefanovic
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009415:Nerve Net / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D055647:Rats, Transgenic; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins