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

Abstract

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 (Aβ)1-42 increased expression of complement C3 mRNA and increased release of C3 protein. Aβ treatment of HCSMC also increased expression of C6 mRNA. Interferon-γ induced expression and release of complement C1r, C1s, C2 and C4. As HCSMC are closely associated with Aβ 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.

Role of Complement Cascade in Abdominal Aortic Aneurysms

“…In another study, human cerebrovascular SMCs expressed mRNA of many complement cascade genes including C1QB, C1R, C1S, C2, C3 and C4 from the classical pathway. 38 Our results demonstrated the presence of the complement proteins C2, CFH, C3, and transcription factor STAT5A in the cells of the aortic wall. Although CFB-mRNA was expressed in AAA tissues, CFB protein was not detectable in aortic wall tissue.…”

A large scale multivariate parallel ICA method reveals novel imaging–genetic relationships for Alzheimer's disease in the ADNI cohort

“…Three such genes were present in component 1. Immune function, especially the complement system, related to amyloid-beta clearance (Guerreiro et al, 2010; Kolev et al, 2009) and expressed in cerebrovascular smooth muscle (Walker et al, 2008), is suggested by ATF7, CFB, C2, SKIV2L, C6orf10 and C6orf15 (Li et al, 2006; Veerhuis, 2010). These genes support the known role of the complement system in LOAD pathogenesis (van Es and van den Berg, 2009), while adding new gene candidates, e.g.…”

Multidimensional plasma protein separation technique for identification of potential Alzheimer’s disease plasma biomarkers: a pilot study

“…CFH was also reported as a blood biomarker for AD disease progression (Hye et al 2006). Complement factors are associated with senile plaques and play a central role in the inflammation process in brains of AD patients (Walker et al 2008;Yasojima et al 1999). SerpinG1 Ser/Cys protease inhibitor and Serpin G1 plasma protease C1 inhibitor control the activity of the complement proteases (Murray-Rust et al 2009).…”