RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease.
Microglia are critical for amyloid-beta peptide (Abeta)-mediated neuronal perturbation relevant to Alzheimer's disease (AD) pathogenesis. We demonstrate that overexpression of receptor for advanced glycation end products (RAGE) in imbroglio exaggerates neuroinflammation, as evidenced by increased proinflammatory mediator production, Abeta accumulation, impaired learning/memory, and neurotoxicity in an Abeta-rich environment. Transgenic (Tg) mice expressing human mutant APP (mAPP) in neurons and RAGE in microglia displayed enhanced IL-1beta and TNF-alpha production, increased infiltration of microglia and astrocytes, accumulation of Abeta, reduced acetylcholine esterase (AChE) activity, and accelerated deterioration of spatial learning/memory. Notably, introduction of a signal transduction-defective mutant RAGE (DN-RAGE) to microglia attenuates deterioration induced by Abeta. These findings indicate that RAGE signaling in microglia contributes to the pathogenesis of an inflammatory response that ultimately impairs neuronal function and directly affects amyloid accumulation. We conclude that blockade of microglial RAGE may have a beneficial effect on Abeta-mediated neuronal perturbation relevant to AD pathogenesis.-Fang, F., Lue, L.-F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., Chen, J. X., Yan, S. S. RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease.
Fang
Fang
F
P&S 17-410, Department Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th St., New York, NY 10032, USA.
Lue
Lih-Fen
LF
Yan
Shiqiang
S
Xu
Hongwei
H
Luddy
John S
JS
Chen
Doris
D
Walker
Douglas G
DG
Stern
David M
DM
Yan
Shifang
S
Schmidt
Ann Marie
AM
Chen
John X
JX
Yan
Shirley ShiDu
SS
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D014409:Tumor Necrosis Factor-alpha; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases