title: Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease.
abstract: Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of β-amyloid (Aβ) transport and degradation. We analyzed BM changes and the pattern of deposition of Aβ in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Aβ was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Aβ deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular β-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Aβ. Impaired β-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Aβ degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Held
authors.affiliation: Faculty of Medicine, University of Southampton, U.K.
authors.forename: Alan W J
authors.initials: AWJ
authors.lastname: Morris
authors.affiliation: Department of Research Methodology, University of Medicine and Pharmacy of Craiova, Romania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pirici
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Solveig
authors.initials: S
authors.lastname: Niklass
authors.affiliation: Faculty of Medicine, University of Southampton, U.K.
authors.forename: Matthew M G
authors.initials: MMG
authors.lastname: Sharp
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Garz
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Assmann
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Hans-Jochen
authors.initials: HJ
authors.lastname: Heinze
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schreiber
authors.affiliation: Faculty of Medicine, University of Southampton, U.K.
authors.forename: Roxana Octavia
authors.initials: RO
authors.lastname: Carare
authors.affiliation: Department of Neurology, Otto-von-Guericke University Magdeburg, Germany, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany stefanie.schreiber@med.ovgu.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism; D059345:Cerebral Small Vessel Diseases / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D055806:Microvessels / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides
keywords: cerebral amyloid angiopathy; cerebral small vessel disease; perivascular Aβ drainage; spontaneously hypertensive animal model