title: White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies.
abstract: We investigated cognitive function, axonal/white matter (WM) changes and glymphatic function of vascular dementia using a multiple microinfarction (MMI) model in retired breeder (RB) rats. The MMI model induces significant (p < 0.05) cognitive decline that worsens with age starting at 2 weeks, which persists until at least 6 weeks after MMI. RB rats subjected to MMI exhibit significant axonal/WM damage identified by decreased myelin thickness, oligodendrocyte progenitor cell numbers, axon density, synaptic protein expression in the cortex and striatum, cortical neuronal branching, and dendritic spine density in the cortex and hippocampus compared with age-matched controls. MMI evokes significant dilation of perivascular spaces as well as water channel dysfunction indicated by decreased Aquaporin-4 expression around blood vessels. MMI-induced glymphatic dysfunction with delayed cerebrospinal fluid penetration into the brain parenchyma via paravascular pathways as well as delayed waste clearance from the brain. The MMI model in RB rats decreases Aquaporin-4 and induces glymphatic dysfunction which may play an important role in MMI-induced axonal/WM damage and cognitive deficits.
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA; Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Poornima
authors.initials: P
authors.lastname: Venkat
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA; Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Cui
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Qingjiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Talan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Liu
authors.affiliation: Neurology Research, Henry Ford Hospital, Detroit, MI, USA; Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China. Electronic address: jieli@neuro.hfh.edu.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000378:metabolism; D003071:Cognition; D015140:Dementia, Vascular / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D008208:Lymphatic System / Q000502:physiology*; D008297:Male; D009186:Myelin Sheath / Q000473:pathology; D009457:Neuroglia / Q000502:physiology*; D009836:Oligodendroglia / Q000473:pathology; D017208:Rats, Wistar; D066127:White Matter / Q000473:pathology*
chemical_list: C496032:Aqp4 protein, rat; D051401:Aquaporin 4
keywords: Aquaporin-4; Glymphatic system; Multiple microinfarction; Vascular dementia; White matter