Amylin Treatment Reduces Neuroinflammation and Ameliorates Abnormal Patterns of Gene Expression in the Cerebral Cortex of an Alzheimer's Disease Mouse Model.
JOURNAL OF ALZHEIMERS DISEASE(2017)
摘要
Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.
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关键词
Alzheimer's disease,amylin,hub gene,transcriptome,WGCNA
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