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• W2897861520 abstract "Sex differences in the effect of ApoE4 on risk and progression of AD have been reported, with greater adverse impact in women. To address sex and APOE genotype impact on therapeutic efficacy of the regenerative neurosteroid Allopregnanolone (Allo), we investigated behavioral and metabolomic outcomes following Allo treatment in aged APOE4-/+ female and male mice. Female and male ApoE3, E4 E3/4 mice were treated 1/week with intramuscular dose of 2 mg/kg Allo for 26 weeks or placebo from 10-16 months-of-age. Dose, formulation and duration of treatment were designed to reflect the human Phase 1b/2a clinical trial of Allo, (ClinicalTrials.gov ID: NCT02221622). Behavior was assessed using Novel Object Recognition. Plasma and cortex were queried for 185 metabolites using ultra-performance-LCMS. Behavioral analyses indicated significantly increased novel object recognition in ApoE4 females and males with greatest effect in ApoE4 females, higher Discrimination Index (DI) and significantly better novel object recognition. Allo had no effect in APOE3/3 mice. Metabolomic analyses indicated changes in lipid and Arg metabolism between females and males within and across the three genotypes. In ApoE3 and ApoE4 females, plasma glycerophospholipid metabolism was significantly downregulated (p<0.05). Glycerophospholipids were lowest in ApoE3/4 females. In cortex, biogenic amines (α-aminoadipic acid, putrescine) and amino acids (Arg and Phe) were lowest in ApoE3 and ApoE4 females suggesting increased Arg catabolism. Following Allo treatment, ApoE4 female plasma showed decreased glycerophospholipids and increased acylcarnitines, suggesting increased lipid catabolism. In ApoE4 male plasma, Allo increased ADMA, ornithine, and acylcarnitines, indicating increased Arg and lipid catabolism. Allo exerted an APOE genotype dependent effect to improve cognitive function in ApoE4+ female and male mice with ApoE4+females exhibiting greater response to Allo. Metabolomic data are suggestive of an effect of Allo to increase lipid metabolism to generate acetyl-CoA to feed into the TCA cycle ATP generation in the mitochondria. Further, Allo treatment increased indicators of protein metabolism. In summary, efficacy of Allo was evident in both females and males and modified by ApoE genotype. Further therapeutic development of Allo is underway." @default.
• W2897861520 created "2018-10-26" @default.
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• W2897861520 date "2018-07-01" @default.
• W2897861520 modified "2023-10-16" @default.
• W2897861520 title "P2‐129: ALLOPREGNANOLONE RESTORES COGNITIVE FUNCTION IN APOE4+ FEMALES AND MALES AND PROMOTES METABOLISM OF FUELS REQUIRED FOR ATP GENERATION" @default.
• W2897861520 doi "https://doi.org/10.1016/j.jalz.2018.06.815" @default.
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