Activated scavenger receptor A promotes glial internalization of aβ.
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.
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.
He
H
Zhang
School of Life Science, Ningxia University, Yinchuan, China.
Ya-jing
YJ
Su
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.
Wei-wei
WW
Zhou
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.
Shao-wei
SW
Wang
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.
Peng-xin
PX
Xu
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.
Xiao-lin
XL
Yu
National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.
Rui-tian
RT
Liu
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001254:Astrocytoma / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D051116:Receptors, Scavenger / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; C495139:MSR1 protein, human; D008565:Membrane Proteins; C495140:Msr1 protein, mouse; D010446:Peptide Fragments; D010455:Peptides; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D014409:Tumor Necrosis Factor-alpha; C574897:XD4 peptide; C075222:amyloid beta-protein (1-42)