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• W2897664441 abstract "Emerging treatments for Alzheimer's disease (AD) focus on developing disease-modifying therapies that attempt to slow and/or prevent disease progression. Considerable evidence suggest that the amyloid beta (Aβ) plaques and other noxious stimuli promote a disproportionate increase in activated nuclear factor-kappa B (NF-κB) p65 dimers and mediate neuroinflammation leading to neurodegeneration. We identified a novel strategy to target activated p65. Glucocorticoid induced leucine zipper (GILZ) is a NF-κB interacting protein that binds the transactivation domain (TAD) of p65 and sequesters it in the cytoplasm. We developed rationally designed peptide analogs of the p65 binding domain of GILZ such that the analogs exhibit near native docking and optimal binding kinetics with p65-TAD. We showed that select GILZ analogs (GA) inhibited Aβ induced metabolic activity and inflammatory cytokines in human mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in a neuroinflammation model of AD. GA and control peptides (CP) were synthesized covalently with the cell-penetrating agent as peptide amides with amino terminal acetylation. Adult C57Bl/6J mice were injected lipopolysaccharide (LPS) intraperitoneally at 250mg/kg daily for 7 days. Groups of mice were administered intravenously either GA-1 or GA-2 or CP-1 or CP-2 or CP-3 at 25 mg/kg on alternate days. All mice were sacrificed on day 8 by intracardial perfusion and brain tissues were harvested. The densities of microglial cells, astrocytes and activated p65 were assessed by immunohistochemistry and image analyses. The proportion of activated NF-κB p65, the concentration of inflammatory cytokines and that of apoptosis mediators in brain tissues were determined by enzyme linked immunosorbent assay and real time polymerase chain reaction. Fewer microglial cells and astrocytes were observed in the brain of mice treated with GA-1 or GA-2. The concentration of inflammatory cytokines was significantly lower and that of anti-apoptotic factors was higher in mice induced neuroinflammation and treated with GA-1 or GA-2. The inhibitory effects of GA could be attributed to the observed reduction in activated p65 in brain tissues. The ability of GA to suppress gliosis, inflammation and upregulate survival suggest that these novel peptides have significant therapeutic potential in AD." @default.
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• W2897664441 date "2018-07-01" @default.
• W2897664441 modified "2023-10-16" @default.
• W2897664441 title "P3‐050: GLUCOCORTICOID‐INDUCED LEUCINE ZIPPER ANALOGS SUPPRESS NEUROINFLAMMATION IN ALZHEIMER'S DISEASE" @default.
• W2897664441 doi "https://doi.org/10.1016/j.jalz.2018.06.1405" @default.
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