title: Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease.
abstract: BACKGROUND
  Cerebral small vessel disease (cSVD) is one of the most prevalent neurological disorders. The progressive remodeling of brain microvessels due to arterial hypertension or other vascular risk factors causes subtle, but constant cognitive decline through to manifest dementia and substantially increases the risk for stroke. Preliminary evidence suggests the contribution of the immune system to disease initiation and progression, but a more detailed understanding is impaired by the unavailability of appropriate animal models. Here, we introduce the spontaneously hypertensive rat (SHR) as a model for early onset cSVD and unveiled substantial immune changes in conjunction with brain abnormalities that resemble clinical findings.
  
  
  RESULTS
  In contrast to age-matched normotensive Wistar Kyoto (WKY) rats, male SHR exhibited non-spatial memory deficits. Magnetic resonance imaging showed brain atrophy and a reduction of white matter volumes in SHR. Histological analyses confirmed white matter demyelination and unveiled a circumscribed blood brain barrier dysfunction in conjunction with micro- and macrogliosis in deep cortical regions. Flow cytometry and histological analyses further revealed substantial disparities in cerebral CD45high leukocyte counts and distribution patterns between SHR and WKY. SHR showed lower counts of T cells in the choroid plexus and meningeal spaces as well as decreased interleukin-10 levels in the cerebrospinal fluid. On the other hand, both T and NK cells were significantly augmented in the SHR brain microvasculature.
  
  
  CONCLUSIONS
  Our results indicate that SHR share behavioral and neuropathological characteristics with human cSVD patients and further undergird the relevance of immune responses for the initiation and progression of cSVD.
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. daniel.kaiser@izi.fraunhofer.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaiser
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. gesa.weise@izi.fraunhofer.de.|Department of Neurology, University of Leipzig, Leipzig, Germany. gesa.weise@izi.fraunhofer.de.|Translational Centre for Regenerative Medicine, Leipzig, Germany. gesa.weise@izi.fraunhofer.de.
authors.forename: Gesa
authors.initials: G
authors.lastname: Weise
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. karoline.moeller@izi.fraunhofer.de.
authors.forename: Karoline
authors.initials: K
authors.lastname: Möller
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. johanna.scheibe@izi.fraunhofer.de.
authors.forename: Johanna
authors.initials: J
authors.lastname: Scheibe
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. claudia.poesel@izi.fraunhofer.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pösel
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. sebastian.baasch@izi.fraunhofer.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Baasch
authors.affiliation: Department of Radiology, University of Leipzig, Leipzig, Germany. Matthias.Gawlitza@medizin.uni-leipzig.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gawlitza
authors.affiliation: Department of Neuroradiology, University of Leipzig, Leipzig, Germany. donald.lobsien@medizin.uni-leipzig.de.
authors.forename: Donald
authors.initials: D
authors.lastname: Lobsien
authors.affiliation: Department of Neurology, University of Münster, Münster, Germany. kai.diederich@uni-muenster.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Diederich
authors.affiliation: Department of Neurology, University of Münster, Münster, Germany. minnerup@uni-muenster.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Minnerup
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. alexander.kranz@izi.fraunhofer.de.|Translational Centre for Regenerative Medicine, Leipzig, Germany. alexander.kranz@izi.fraunhofer.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kranz
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. johannes.boltze@izi.fraunhofer.de.|Translational Centre for Regenerative Medicine, Leipzig, Germany. johannes.boltze@izi.fraunhofer.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Boltze
authors.affiliation: Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103, Leipzig, Germany. daniel-christoph.wagner@izi.fraunhofer.de.|Translational Centre for Regenerative Medicine, Leipzig, Germany. daniel-christoph.wagner@izi.fraunhofer.de.
authors.forename: Daniel-Christoph
authors.initials: DC
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001284:Atrophy; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D059345:Cerebral Small Vessel Diseases / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005911:Gliosis / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000134:cerebrospinal fluid; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000276:immunology / Q000473:pathology; D015213:Neuroimmunomodulation / Q000502:physiology*; D009929:Organ Size; D011897:Random Allocation; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D066127:White Matter / Q000473:pathology* / Q000503:physiopathology
chemical_list: D016753:Interleukin-10; D017493:Leukocyte Common Antigens; C516771:Ptprc protein, rat