Activated scavenger receptor A promotes glial internalization of aβ

He Zhang; Ya-jing Su; Wei-wei Zhou; Shao-wei Wang; Peng-xin Xu; Xiao-lin Yu; Rui-tian Liu

doi:10.1371/journal.pone.0094197

Activated scavenger receptor A promotes glial internalization of aβ

PLoS One. 2014 Apr 9;9(4):e94197. doi: 10.1371/journal.pone.0094197. eCollection 2014.

Authors

He Zhang¹, Ya-jing Su², Wei-wei Zhou³, Shao-wei Wang³, Peng-xin Xu³, Xiao-lin Yu³, Rui-tian Liu³

Affiliations

¹ National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China; Tsinghua University School of Medicine, Haidian District, Beijing, China.
² School of Life Science, Ningxia University, Yinchuan, China.
³ National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.

Abstract

Beta-amyloid (Aβ) aggregates have a pivotal role in pathological processing of Alzheimer's disease (AD). The clearance of Aβ monomer or aggregates is a causal strategy for AD treatment. Microglia and astrocytes are the main macrophages that exert critical neuroprotective roles in the brain. They may effectively clear the toxic accumulation of Aβ at the initial stage of AD, however, their functions are attenuated because of glial overactivation. In this study, we first showed that heptapeptide XD4 activates the class A scavenger receptor (SR-A) on the glia by increasing the binding of Aβ to SR-A, thereby promoting glial phagocytosis of Aβ oligomer in microglia and astrocytes and triggering intracellular mitogen-activated protein kinase (MAPK) signaling cascades. Moreover, XD4 enhances the internalization of Aβ monomers to microglia and astrocytes through macropinocytosis or SR-A-mediated phagocytosis. Furthermore, XD4 significantly inhibits Aβ oligomer-induced cytotoxicity to glial cells and decreases the production of proinflammatory cytokines, such as TNF-α and IL-1β, in vitro and in vivo. Our findings may provide a novel strategy for AD treatment by activating SR-A.

Publication types

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

MeSH terms

Amyloid beta-Peptides / metabolism*
Animals
Astrocytes / drug effects
Astrocytes / metabolism*
Astrocytoma / pathology
Cell Line
Cell Line, Tumor
Cells, Cultured
Cerebral Cortex / cytology
Drug Evaluation, Preclinical
Humans
Interleukin-1beta / metabolism
Membrane Proteins / metabolism
Mice
Microglia / drug effects
Microglia / metabolism*
Peptide Fragments / metabolism*
Peptides / pharmacology*
Phagocytosis / drug effects
Rats
Receptors, Scavenger / physiology*
Scavenger Receptors, Class A / physiology*
Tumor Necrosis Factor-alpha / metabolism

Substances

Amyloid beta-Peptides
Interleukin-1beta
MSR1 protein, human
Membrane Proteins
Msr1 protein, mouse
Peptide Fragments
Peptides
Receptors, Scavenger
Scavenger Receptors, Class A
Tumor Necrosis Factor-alpha
XD4 peptide
amyloid beta-protein (1-42)

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (30971012 and 81171014) and the National Science and Technology Major Projects of New Drugs (2012ZX09103301-001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.