title: A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer's disease brain.
abstract: This study has used immunohistochemical examination of tissue obtained from Alzheimer's disease (AD) brains and rat hippocampus injected with Abeta(1-42) peptide to determine effects of induced inflammatory reactivity on integrity of blood-brain barrier (BBB) and viability of neurons. Tissue from AD, but not non-demented, brains exhibited a diffuse pattern of staining for fibrinogen and immunoglobulin (IgG) indicative of BBB leakiness with considerable fibrinogen immunoreactivity (ir) appearing in association with Abeta deposits. Immunostaining for the endothelial cell specific glycoprotein, von Willebrand factor, showed morphological evidence for altered blood vessels in AD tissue. AD brains also demonstrated extensive areas of fibrinogen ir in association with microglial reactivity. In vivo, intra-hippocampal injection of Abeta(1-42) caused time-dependent (1-7 days after injection) increases in double staining of fibrinogen with areas of microgliosis. Two independent pharmacological strategies were employed to examine how Abeta(1-42) stimulation (7 days injection) may be linked to neurodegeneration. The defibrinogenating compound, ancrod, reduced inflammatory reactivity, levels of parenchymal fibrinogen and IgG, and was neuroprotective. These results prompted use of Abeta(1-42) plus fibrinogen as a novel in vivo inflammatory stimulus and this combination significantly enhanced inflammatory reactivity, vascular perturbations and neuronal damage compared to Abeta(1-42) alone. A second approach, using anti-Mac-1 (antibody for antigen CD11b) to block activation of microglia, was highly effective in attenuating effects of Abeta(1-42) plus fibrinogen amplification of inflammatory and vascular responses and conferred significant neuroprotection. The overall findings from study of AD tissue and in vivo in Abeta(1-42) and Abeta(1-42) plus fibrinogen stimulated rat hippocampus suggest microglial responses to promote increased extravasation of blood protein as a critical component in amplifying inflammatory reactivity and causing neuronal damage in inflamed AD brain.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Ryu
authors.forename: James G
authors.initials: JG
authors.lastname: McLarnon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000721:Ancrod / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003704:Dementia / Q000150:complications / Q000473:pathology; D005340:Fibrinogen / Q000378:metabolism*; D005453:Fluorescence; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014841:von Willebrand Factor; D005340:Fibrinogen; D000721:Ancrod