Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: a potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease.
Deposition of amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA), is a major pathological feature found in the majority of Alzheimer's disease (AD) cases, and activated complement fragments have been detected on CAA deposits in AD brains. In this study, we demonstrate for the first time that human cerebrovascular smooth muscle cells (HCSMC) isolated from cortical vessels derived from postmortem brains can express mRNAs for complement genes C1qB, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9, the components of the classical complement pathway. Secretion of the corresponding complement proteins for these genes was also demonstrated, except for C1q and C5. Of particular significance was the observation that treatment of HCSMC with aggregated amyloid beta (Abeta) 1-42 increased expression of complement C3 mRNA and increased release of C3 protein. Abeta treatment of HCSMC also increased expression of C6 mRNA. Interferon-gamma induced expression and release of complement C1r, C1s, C2 and C4. As HCSMC are closely associated with Abeta deposits in vessels in the brain, their production of complement proteins could amplify the proinflammatory effects of amyloid in the perivascular environment, further compromising brain vascular integrity.
Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, Arizona, USA. douglas.walker@sunhealth.org
Douglas G
DG
Walker
Jessica E
JE
Dalsing-Hernandez
Lih-Fen
LF
Lue
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D001921:Brain / Q000098:blood supply*; D002102:Cadaver; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism* / Q000473:pathology; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000378:metabolism
D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D007371:Interferon-gamma; D003165:Complement System Proteins