This study has used immunohistochemical examination of tissue obtained from Alzheimer’s disease (AD) brains and rat hippocampus injected with Aβ_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 Aβ 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 Aβ_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 Aβ_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 Aβ_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 Aβ_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 Aβ_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 Aβ_1‐42 and Aβ_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.