RESUMO
Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-ß peptide (Aß) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aß, decreased plasma soluble Aß, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1ß, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aß phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aß 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(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aß oligomers and validate CD45-mediated microglial clearance of oligomeric Aß as a novel AD therapeutic target.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antígenos Comuns de Leucócito/genética , Neurônios/patologia , Fragmentos de Peptídeos/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Barreira Hematoencefálica/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Microglia/imunologia , Microglia/patologia , Mitocôndrias/metabolismo , Neurônios/metabolismo , Presenilina-1/genética , Multimerização Proteica , Transgenes , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Extracellular plaques of beta-amyloid (Abeta) peptides are implicated in Alzheimer's Disease (AD) pathogenesis. Abeta formation is precluded by alpha-secretase, which cleaves within the Abeta domain of APP generating soluble APP-alpha (sAPP-alpha). Thus, alpha-secretase upregulation may be a target AD therapy. We previously showed green tea derived EGCG increased sAPP-alpha in AD mouse models. However, the comparable effective dose of EGCG in humans may exceed clinical convenience and/or safety. Epidemiological studies suggested fish oil consumption is associated with reduced dementia risk. Here we investigated whether oral co-treatment with fish oil (8mg/kg/day) and EGCG (62.5mg/kg/day or 12.5mg/kg/day) would reduce AD-like pathology in Tg2576 mice. In vitro co-treatment of N2a cells with fish oil and EGCG enhanced sAPP-alpha production compared to either compound alone (P<0.001). Fish oil enhanced bioavailability of EGCG versus EGCG treatment alone (P<0.001). Fish oil and EGCG had a synergetic effect on inhibition of cerebral Abeta deposits (P<0.001) suggesting moderate supplementation with EGCG and fish oil having significant therapeutic potential for the treatment of AD.