Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

被引:324
作者
Yan, SD
Zhu, HJ
Fu, J
Yan, SF
Roher, A
Tourtellotte, WW
Rajavashisth, T
Chen, X
Godman, GC
Stern, D
Schmidt, AM
机构
[1] COLUMBIA UNIV,COLL PHYS & SURG,DEPT SURG,NEW YORK,NY 10032
[2] COLUMBIA UNIV,COLL PHYS & SURG,DEPT PHYSIOL,NEW YORK,NY 10032
[3] COLUMBIA UNIV,COLL PHYS & SURG,DEPT MED,NEW YORK,NY 10032
[4] SUN HLTH RES INST,HALDEMAN LAB ALZHEIMERS DIS RES,SUN CITY,AZ 85372
[5] W LOS ANGELES VET AFFAIRS MED CTR,NATL NEUROL RES SPECIMEN BANK,LOS ANGELES,CA 90073
[6] UNIV CALIF LOS ANGELES,LOS ANGELES CTY HARBOR MED CTR,SCH MED,TORRANCE,CA 90502
关键词
microglia; neurons; cerebrospinal fluid;
D O I
10.1073/pnas.94.10.5296
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia, We demonstrate that binding of amyloid-beta peptide (A beta) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A beta, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor kappa B-dependent pathway, AD brain shows increased neuronal expression of M-CSF in proximity to A beta deposits, and in cerebrospinal fluid from AD patients there was approximate to 5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls, M-CSF released by A beta-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A beta, consistent with pathologic findings in AD, These data delineate an inflammatory pathway triggered by engagement of A beta on neuronal RAGE, We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.
引用
收藏
页码:5296 / 5301
页数:6
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