title: Cerebrovascular pathology during the progression of experimental Alzheimer's disease.
abstract: Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aβ accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aβ accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRβ) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aβ plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRβ(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRβ(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannoni
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors.forename: Ines Das
authors.initials: ID
authors.lastname: Neves
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rousset
authors.affiliation: NICN, Aix-Marseille Université, CNRS, UMR7259, Marseille, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Baranger
authors.affiliation: NICN, Aix-Marseille Université, CNRS, UMR7259, Marseille, France.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rivera
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors.forename: Freddy
authors.initials: F
authors.lastname: Jeanneteau
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France. Electronic address: sylvie.claeysen@igf.cnrs.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Claeysen
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Inserm, U1191, F-34000 Montpellier, France; Université de Montpellier, UMR-5203, F-34000 Montpellier, France. Electronic address: nicola.marchi@igf.cnrs.fr.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000235:genetics*; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053764:Presenilin-1 / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D024141:Collagen Type IV; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053764:Presenilin-1; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: 5xFAD; Alzheimer; CAA; Microvascular inflammation