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.