C1 Complement mediates human cord blood serum derived APP α-secretase cleavage activity in vitro

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In healthy individual amyloid precursor protein (APP) is cleaved by α-secretase generating sAPPα. However, in the neurodegenerative environment of AD patients, Aß peptides of either 40 or 42 residues are generated by increased beta and gamma secretase activity. Human umbilical cord blood cells (UCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases. Our study investigated the impact of UCBS on modulation of sAPPα production. Heat-activated UCBS has significantly promoted sAPPα production indicating presence of heat sensitive α-secretase in CBS. Using LC-MS/MS, We identified the subunits of C1 complex (C1q, C1r and C1s) and α-2-macroglobulin showed significantly greater levels in αCBSF compared with AgBSF. Specifically, C1 markedly increased sAPPα and αCTF production, whereas C1q alone only minimally increased and C3 did not increase sAPPα production in the absence of sera. Furthermore, C1q markedly increased sAPPα and αCTF, while decreasing Aß, in CHO/APPwt cells cultured in the presence of whole sera. These results confirm that APP α-secretase activity in human blood serum is mediated by C1 opening a potential modality of therapeutic for the future of AD.