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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 α-secretase, generating soluble α-amyloid precursor protein (sAPPα), which contributes neuroprotective functions in the neuronal environment. In contrast, i...

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Autores principales: Habib, Ahsan, Sawmiller, Darrell, Hou, Huayan, Kanithi, Manasa, Tian, Jun, Zeng, Jin, Zi, Dan, He, Zhi-Xu, Sanberg, Paul R., Tan, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020233/
https://www.ncbi.nlm.nih.gov/pubmed/29871524
http://dx.doi.org/10.1177/0963689718775941
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author Habib, Ahsan
Sawmiller, Darrell
Hou, Huayan
Kanithi, Manasa
Tian, Jun
Zeng, Jin
Zi, Dan
He, Zhi-Xu
Sanberg, Paul R.
Tan, Jun
author_facet Habib, Ahsan
Sawmiller, Darrell
Hou, Huayan
Kanithi, Manasa
Tian, Jun
Zeng, Jin
Zi, Dan
He, Zhi-Xu
Sanberg, Paul R.
Tan, Jun
author_sort Habib, Ahsan
collection PubMed
description 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.
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spelling pubmed-70202332020-02-27 Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement Habib, Ahsan Sawmiller, Darrell Hou, Huayan Kanithi, Manasa Tian, Jun Zeng, Jin Zi, Dan He, Zhi-Xu Sanberg, Paul R. Tan, Jun Cell Transplant Original Articles 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. SAGE Publications 2018-06-05 2018-04 /pmc/articles/PMC7020233/ /pubmed/29871524 http://dx.doi.org/10.1177/0963689718775941 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Articles
Habib, Ahsan
Sawmiller, Darrell
Hou, Huayan
Kanithi, Manasa
Tian, Jun
Zeng, Jin
Zi, Dan
He, Zhi-Xu
Sanberg, Paul R.
Tan, Jun
Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title_full Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title_fullStr Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title_full_unstemmed Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title_short Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement
title_sort human cord blood serum-derived app α-secretase cleavage activity is mediated by c1 complement
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020233/
https://www.ncbi.nlm.nih.gov/pubmed/29871524
http://dx.doi.org/10.1177/0963689718775941
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