| Abstract: |
Microglia are critical for amyloid-β peptide (Aβ)-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, Aβ accumulation, impaired learning/memory, and neurotoxicity in an Aβ-rich environment. Transgenic (Tg) mice expressing human mutant APP (mAPP) in neurons and RAGE in microglia displayed enhanced IL-1β and TNF-α production, increased infiltration of microglia and astrocytes, accumulation of Aβ, 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 Aβ. 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 Aβ-mediated neuronal perturbation relevant to AD pathogenesis. © FASEB. |
| Keywords: |
signal transduction; mitogen activated protein kinase; controlled study; promoter region; genetics; mutation; pathogenesis; nonhuman; neurotoxicity; mouse; animal; metabolism; animals; mice; animal tissue; cell infiltration; interleukin 1beta; animal experiment; animal model; astrocyte; inflammation; protein binding; neurons; pathology; enzyme activity; tumor antigen; transgenic mouse; animalia; mus musculus; mice, transgenic; disease model; cytokine; tumor necrosis factor alpha; antigens, neoplasm; tumor necrosis factor-alpha; memory disorder; memory; disease models, animal; mitogen-activated protein kinases; nerve function; nerve cell; alzheimer disease; neuropathology; astrocytes; learning; amyloid beta-protein; acetylcholinesterase; interleukin-1beta; amyloid beta protein; aβ-binding protein; microglia/neuron interaction; advanced glycation end product receptor; rage protein, human; rage protein, mouse; learning disorder; microglia
|
