Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement.

Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein (APP) is cleaved by alpha-secretase, generating soluble alpha-amyloid precursor protein (sAPP alpha), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-beta-peptide (A beta) of either 40 or 42 residues are generated by increased activity of beta- and gamma-secretase. These proteins amalgamate in specific regions of the brain, which disrupts neuronal functions and leads to cognitive impairment. Human umbilical cord blood cells (HUCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases, including AD. Our most recent work studied the impact of umbilical cord blood serum (CBS) on modulation of sAPP alpha production. Heat-sensitive CBS significantly promoted sAPP alpha production, indicating that heat-sensitive factor(s) play(s) a role in this process. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to determine the molecular source of alpha-secretase in purified CBS and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of CI complex (CIq, CIr, and CIs) and alpha-2-macroglobulin showed significantly greater levels in purified alpha-CBS fraction (alpha-CBSF) compared with the AgBS fraction (AgBSF). Specifically, CI markedly increased sAPP alpha and alpha-carboxyl-terminal fragment (alpha-CTF) production in a dose-dependent fashion, whereas CIq alone only minimally increased and C3 did not increase sAPP alpha production in the absence of sera. Furthermore, CIq markedly increased sAPP alpha and alpha-CTF, while decreasing A beta, in CHO/PPwt cells cultured in the presence of whole sera. These results confirm our initial assumption that APP alpha-secretase activity in human blood serum is mediated by complement CI, opening a potential therapeutic modality for the future of AD.