MFG-E8 inhibits Aβ-induced microglial production of cathelicidin-related antimicrobial peptide: A suitable target against Alzheimer's disease

Xiaotian Xu; Xiaoying Cai; Yingting Zhu; Wen He; Qi Wu; Xiaolei Shi; Yannan Fang; Zhong Pei

doi:10.1016/j.cellimm.2018.05.008

MFG-E8 inhibits Aβ-induced microglial production of cathelicidin-related antimicrobial peptide: A suitable target against Alzheimer's disease

Cell Immunol. 2018 Sep:331:59-66. doi: 10.1016/j.cellimm.2018.05.008. Epub 2018 May 24.

Authors

Xiaotian Xu¹, Xiaoying Cai², Yingting Zhu³, Wen He¹, Qi Wu¹, Xiaolei Shi⁴, Yannan Fang⁵, Zhong Pei¹

Affiliations

¹ Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, People's Republic of China.
² Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, People's Republic of China.
³ State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
⁴ Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada; Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province 241000, People's Republic of China. Electronic address: shixiaolei05@gmail.com.
⁵ Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, People's Republic of China. Electronic address: fyn2012@126.com.

PMID: 29861070
DOI: 10.1016/j.cellimm.2018.05.008

Abstract

Neuroinflammation plays a pivotal role in the incidence and progression of Alzheimer's disease (AD). Cathelicidin-related antimicrobial peptide (CRAMP) is critically involved in the innate neuronal responses of chronic neuroinflammation in AD and thus plays a key role in the disease. Here, we show that Aβ42 induced microglial production of CRAMP, which was effectively inhibited by milk-fat globule-epidermal growth factor 8 (MFG-E8). Production of CRAMP was associated with activation of ERK1/2, p38 and phospho-P65-NF-kB upregulation. Additionally, the phosphorylation of these signaling proteins was also reversed by MFG-E8. Pre-incubation with signaling inhibitors confirmed that MFG-E8 has a regulatory role on CRAMP through MAPK and NF-kB signaling pathways. MFG-E8 treatment may thus be a potential pharmacotherapy for chronic inflammation in AD.

Keywords: Alzheimer’s disease; Aβ42; CRAMP; MFG-E8; Microglia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Amyloid beta-Peptides / toxicity*
Animals
Animals, Newborn
Antigens, Surface / pharmacology*
Antimicrobial Cationic Peptides / antagonists & inhibitors*
Antimicrobial Cationic Peptides / genetics
Antimicrobial Cationic Peptides / metabolism
Cathelicidins
Cells, Cultured
Gene Expression / drug effects
Inflammation / drug therapy
Inflammation / genetics
Inflammation / metabolism
Mice, Inbred C57BL
Microglia / drug effects*
Microglia / metabolism
Milk Proteins / pharmacology*
Mitogen-Activated Protein Kinases / metabolism
NF-kappa B / metabolism
Peptide Fragments / toxicity*
Phosphorylation / drug effects
Signal Transduction / drug effects

Substances

Amyloid beta-Peptides
Antigens, Surface
Antimicrobial Cationic Peptides
Mfge8 protein, mouse
Milk Proteins
NF-kappa B
Peptide Fragments
amyloid beta-protein (1-42)
Mitogen-Activated Protein Kinases
Cathelicidins