title: A shift in microglial β-amyloid binding in Alzheimer's disease is associated with cerebral amyloid angiopathy.
abstract: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are two common pathologies associated with β-amyloid (Aβ) accumulation and inflammation in the brain; neither is well understood. The objective of this study was to evaluate human post-mortem brains from AD subjects with purely parenchymal pathology, and those with concomitant CAA (and age-matched controls) for differential expression of microglia-associated Aβ ligands thought to mediate Aβ clearance and the association of these receptors with complement activation. Homogenates of brain parenchyma and enriched microvessel fractions from occipital cortex were probed for levels of C3b, membrane attack complex (MAC), CD11b and α-2-macroglobulin and immunoprecipitation was used to immunoprecipitate (IP) CD11b complexed with C3b and Aβ. Both C3b and MAC were significantly increased in CAA compared to AD-only and controls and IP showed significantly increased CD11b/C3b complexes with Aβ in AD/CAA subjects. Confocal microscopy was used to visualize these interactions. MAC was remarkably associated with CAA-affected blood vessels compared to AD-only and control vessels. These findings are consistent with an Aβ clearance mechanism via microglial CD11b that delivers Aβ and C3b to blood vessels in AD/CAA, which leads to Aβ deposition and propagation of complement to the cytolytic MAC, possibly leading to vascular fragility.
authors.affiliation: Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zabel
authors.forename: Matthew
authors.initials: M
authors.lastname: Schrag
authors.forename: Andrew
authors.initials: A
authors.lastname: Crofton
authors.forename: Spencer
authors.initials: S
authors.lastname: Tung
authors.forename: Pierre
authors.initials: P
authors.lastname: Beaufond
authors.forename: Jon
authors.initials: J
authors.lastname: Van Ornam
authors.forename: Angielee
authors.initials: A
authors.lastname: Dininni
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Wolff M
authors.initials: WM
authors.lastname: Kirsch
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D017628:Microglia / Q000378:metabolism*; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000682:Amyloid; D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D039481:CD11b Antigen; D015938:Complement Membrane Attack Complex; D010446:Peptide Fragments; D011951:Receptors, Complement; C078592:amyloid beta-protein (1-40)