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- W2897984211 abstract "Late onset Alzheimer's disease (LOAD) is a systemic disease with multiple etiologies, and is associated with compromised brain metabolism and regenerative capacity. Allopregnanolone has been shown to promote brain mitochondrial function, neurogenesis, and memory in mouse models, and is currently being investigated as a regenerative therapeutic for AD (NCT02221622). While genetic markers such as APOE genotype may predict risk of AD, there is currently no genetic markers to predict therapeutic outcomes for AD. Because mitochondrial genetic variances and APOE genotype are known to be differentially associated with respiratory capacity and cell proliferation, in this study, we evaluate whether they can be used as potential genetic markers to predict responders for Alzheimer's disease therapeutics. T-cells from allopregnanolone clinical trial participants were reprogrammed to iPSCs via a non-integrating, non-viral method, and then differentiated into NSCs using dual inhibition of SMAD signaling. Mitochondrial respiration and regenerative capacity were determined by metabolic analyzer and FACS. To determine mitochondrial haplogroups of the participants, DNA was extracted from whole blood of the participants, and Hypervariable region 1 and 2 of mitochondrial DNA were amplified, sequenced, and aligned to the Revised Cambridge Reference Sequence. Mitochondrial haplogroup was assigned using HaploGrep2 based on identified variants. Preliminary analysis revealed that allopregnanolone treatment preferentially increased maximum respiration in NSCs derived from participants of mitochondrial haplogroups M2, M8 and N9 compared to those from haplogroups H, HV, and J. Regardless of mitochondrial haplotype, allopregnanolone induced greater mitochondrial respiration in NSCs derived from APOE 3/4 participants relative to NSCs derived from APOE 3/3 participants. Further, NSCs derived from male APOE4 carriers exhibited significantly different proliferation patterns relative to non-APOE4 carriers following allopregnanolone treatment. On going analyses will determine whether mitochondrial haplotype in combination with APOE genotype can serve as predictive biomarkers of response to allopregnanolone. Mitochondrial haplotype in combination with APOE genotype is a promising predictive biomarker approach to identify potential allopregnanolone responders. Predictive biomarkers will significantly contribute to a precision medicine strategy to identify responders to therapeutic agents for Alzheimer's disease. Research supported by NIA grants UF1-AG046148 and P01-AG026572 to RDB." @default.
- W2897984211 created "2018-10-26" @default.
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- W2897984211 date "2018-07-01" @default.
- W2897984211 modified "2023-10-16" @default.
- W2897984211 title "P1‐018: MITOCHONDRIAL HAPLOGROUP IN COMBINATION WITH APOE GENOTYPE AS POTENTIAL PREDICTIVE BIOMARKER TO IDENTIFY RESPONDERS TO REGENERATIVE THERAPEUTIC ALLOPREGNANOLONE FOR ALZHEIMER'S DISEASE" @default.
- W2897984211 doi "https://doi.org/10.1016/j.jalz.2018.06.019" @default.
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