Document Type
Article
Publication Date
2018
Keywords
Alzheimer’s Disease, Aβ, complement C1 complex, complement system, cord blood serum, human umbilical cord blood cell, soluble α-amyloid precursor protein, amyloid precursor protein
Digital Object Identifier (DOI)
https://doi.org/10.1177/0963689718775941
Abstract
Alzheimer’s Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein (APP) is cleaved by α-secretase, generating soluble α-amyloid precursor protein (sAPPα), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-β-peptide (Aβ) of either 40 or 42 residues are generated by increased activity of β- and γ-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 sAPPα production. Heat-sensitive CBS significantly promoted sAPPα 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 α-secretase in purified CBS and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of C1 complex (C1q, C1r, and C1s) and alpha-2-macroglobulin showed significantly greater levels in purified α-CBS fraction (α-CBSF) compared with the AgBS fraction (AgBSF). Specifically, C1 markedly increased sAPPα and alpha-carboxyl-terminal fragment (α-CTF) production in a dose-dependent fashion, whereas C1q alone only minimally increased and C3 did not increase sAPPα production in the absence of sera. Furthermore, C1q markedly increased sAPPα and α-CTF, while decreasing Aβ, in CHO/APPwt cells cultured in the presence of whole sera. These results confirm our initial assumption that APP α-secretase activity in human blood serum is mediated by complement C1, opening a potential therapeutic modality for the future of AD.
Rights Information
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Cell Transplantation, v. 27, issue 4, p. 666-676
Scholar Commons Citation
Habib, Ahsan; Sawmiller, Darrell; Hou, Huayan; Kanithi, Manasa; Tian, Jun; Zeng, Jin; Zi, Dan; He, Zhi-Xu; Sanberg, Paul R.; and Tan, Jun, "Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement" (2018). Neurosurgery and Brain Repair Faculty Publications. 29.
https://digitalcommons.usf.edu/nbr_facpub/29
