title: Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition.
abstract: The deposition of amyloid beta-protein (A beta) in cerebral vasculature, known as cerebral amyloid angiopathy (CAA), is a common pathological feature of Alzheimer's disease and related disorders. In familial forms of CAA single mutations in the A beta peptide have been linked to the increase of vascular A beta deposits accompanied by a strong localized activation of glial cells and elevated expression of neuroinflammatory mediators including complement proteins. We have developed human amyloid-beta precursor protein transgenic mice harboring two CAA A beta mutations (Dutch E693Q and Iowa D694N) that mimic the prevalent cerebral microvascular A beta deposition observed in those patients, and the Swedish mutations (K670N/M671L) to increase A beta production. In these Tg-SwDI mice, we have reported predominant fibrillar A beta along microvessels in the thalamic region and diffuse plaques in cortical region. Concurrently, activated microglia and reactive astrocytes have been detected primarily in association with fibrillar cerebral microvascular A beta in this model. Here we show that three native complement components in classical and alternative complement pathways, C1q, C3, and C4, are elevated in Tg-SwDI mice in regions rich in fibrillar microvascular A beta. Immunohistochemical staining of all three proteins was increased in thalamus, hippocampus, and subiculum, but not frontal cortex. Western blot analysis showed significant increases of all three proteins in the thalamic region (with hippocampus) as well as the cortical region, except C3 that was below detection level in cortex. Also, in the thalamic region (with hippocampus), C1q and C3 mRNAs were significantly up-regulated. These complement proteins appeared to be expressed largely by activated microglial cells associated with the fibrillar microvascular A beta deposits. Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular A beta deposition that is observed in patients with familial CAA.
authors: Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA. William.VanNostrand@stonybrook.edu.
authors: Rong
authors: R
authors: Fan
authors: Kelly
authors: K
authors: DeFilippis
authors: William E
authors: WE
authors: Van Nostrand
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D003181:Complement C4 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D013788:Thalamus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D003176:Complement C3; D003181:Complement C4; D015922:Complement C1q