Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brain.
Injection of Abeta(1-42) peptide into rat hippocampus has been found to induce microglial reactivity and perturbed vasculature in an animal model of inflamed Alzheimer's disease (AD) brain. We report the anti-angiogenic and anti-inflammatory compound, thalidomide, to significantly inhibit peptide-induced vascular changes including endothelial cell proliferation (marker rat endothelial cell antigen-1, RECA-1), angiogenic activity (marker laminin) and leakiness of blood-brain barrier (BBB, marker albumin). Thalidomide also blocked microgliosis and astrogliosis with double immunostaining showing considerable regions of association of activated microglia with vascular remodeling and leaky BBB. Thalidomide inhibition of the glial-derived proinflammatory/angiogenic factor TNF-alpha (tumor necrosis factor-alpha) in Abeta(1-42)-injected brain and also in vitro from peptide-activated human microglia could underly the changes in vascular processes. Thalidomide treatment in vivo was also associated with a significant reduction in hippocampal neuronal loss. Our findings suggest altered cerebral vasculature as an integral component of inflammatory responses with thalidomide an effective inhibitor of gliosis, vascular changes and TNF-alpha leading to neuroprotection in an animal model of inflamed AD brain.
Ryu
Jae K
JK
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
McLarnon
James G
JG
D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides; D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D020533:Angiogenesis Inhibitors; C101134:ESM1 protein, human; D007797:Laminin; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D013792:Thalidomide