Enlargement of Abeta aggregates through chemokine-dependent microglial clustering.
The number of microglia surrounding senile plaques is correlated with the size of plaques in Alzheimer's disease (AD). It is unclear whether more microglia are passively recruited toward larger senile plaques or, conversely, microglia recruited to senile plaques directly contribute to the growth of plaques. In this study, BV-2 microglia were used to delineate the role of microglia in the growth of plaques using time-lapse recording. Aggregated beta amyloid peptide (Abeta)-induced BV-2 microglia to form clusters. The recruitment of BV-2 microglia bearing membrane-adhered Abeta enlarged preexisting Abeta aggregates. The receptors involved in the microglial uptake of Abeta, including integrin, formyl peptide like receptor 1, and scavenger receptors, also mediated the microglial clustering. Neutralization antibodies against chemokines significantly attenuated Abeta-induced microglial clustering and the enlargement of Abeta aggregates. Our results reveal a novel role of microglia in directly increasing the size of Abeta aggregates and suggest the targeting of Abeta-mediated microglial chemotactic migration in developing therapeutic interventions for AD.
Huang
Wei-Chao
WC
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Yen
Feng-Chang
FC
Shiao
Young-Ji
YJ
Shie
Feng-Shiun
FS
Chan
Jin-Lieh
JL
Yang
Cheng-Ning
CN
Sung
Yen-Jen
YJ
Huang
Fong-Lee
FL
Tsay
Huey-Jen
HJ
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016023:Integrins / Q000037:antagonists & inhibitors; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D018625:Microscopy, Atomic Force / Q000379:methods; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D011487:Protein Conformation; D051116:Receptors, Scavenger / Q000037:antagonists & inhibitors; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000906:Antibodies; D018925:Chemokines; D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; D011134:Polysaccharides; D051116:Receptors, Scavenger; D009240:N-Formylmethionine Leucyl-Phenylalanine; C047981:arginyl-glycyl-aspartic acid; C040300:N-formylmethionyl-cycloleucyl-phenylalanine; C007789:fucoidan