A TRANSGENIC MODEL OF ALZHEIMER'S DISEASE

摘要

Evidence indicates dysregulation of the immunoregulatory molecule CD45 occurs in Alzheimer's disease (AD). Transgenic mice overproducing amyloid-ß peptide (?ß) and deficient in CD45 (PSAPP/CD45 T) recapitulate AD neuropathology. Increased cerebral intracellular and extracellular soluble oligomeric and insoluble ?ß, decreased plasma soluble ?ß, increased microglial neurotoxic cytokines TNF-a and I L-1 ß, and neuronal loss were found in PSAPP/CD45T mice compared with CD45-sufficient PSAPP littermates. After CD45 ablation, in vitro and in vivo studies demonstrate a microglial phenotype whereby microglia phagocytose less ?ß but display proinflammatory properties. This microglial activation occurs with elevated ?ß oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45 T mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic ?ß oligomers and validate CD45-mediated microglial clearance of oligomeric ?ß as a novel AD therapeutic target.