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Our major research interests are the elucidation of inflammatory signaling circuits in Alzheimer’s disease (AD) and in age-related macular degeneration (AMD). AD and AMD represent common, progressive degenerative disorders of human neural (HN) and retinal pigment epithelial (RPE) cells, respectively. Oxidative stress, cytokines, high fat-cholesterol (HF-C) diets, the lipid transporter apolipoprotein E4 (apoE4), and aging, are prominent risk factors for the development of AD and AMD (oval at middle left). These risk factors up-regulate a set of stress-sensitive transcription factors that include, prominently, NF-κB. Promoter mapping of the regulatory regions of the gene encoding beta-amyloid precursor protein (βAPP), is enriched in NF-κB binding sites. Micro RNAs (miRNAs) act as highly effective post-transcriptional repressors of gene expression. NF-κB also up-regulates miRNA-146a expression with resultant down-regulation of sortilin-1 (SORL1) and CFH. SORL1 and CFH down-regulation are associated with increased Aβ peptide generation and Aβ peptide-mediated pathogenic events that (1) contributes to amyloid and drusenoid deposition, (2) enhances inflammatory signaling and apoptosis and (3) drives AD/AMD-type change. In a parallel pathogenic circuit miRNA-29a down-regulation induces up-regulation of beta amyloid cleavage enzyme 1 (βACE1) expression. βACE1-mediated cleavage of the polytopic membrane spanning protein βAPP (green ovals) ultimately increases Aβ peptide abundance that further contributes to amyloid and drusen formation and enhanced inflammatory signaling. Vertical up- or down-arrows within boxes indicate up- or down-regulation, respectively; filled light green box indicates potential blocking compounds – highly penetrant antioxidants such as phenyl butyl nitrone (PBN), the essential omega-3 fatty acid DHA, and miRNA and anti-miRNA strategies. We hypothesize that these specific pathways of genetic mis-regulation in human brain and retinal cells lead to an inflammatory response, resulting in apoptotic changes that are direct precursors to early pathological change in both AD and AMD.
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Papers共 447 篇Author StatisticsCo-AuthorSimilar Experts
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World journal of clinical pediatricsno. 2 (2023): 25-37
Biologyno. 6 (2023): 788-788
CRC Press eBookspp.387-404, (2023)
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Frontiers in cell and developmental biology (2023): 1210530
MOLECULESno. 16 (2022): 5123-5123
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