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P2‐131: ANALYSIS OF A FAMILY WITH IDENTICAL TRIPLETS DISCORDANT FOR ALZHEIMER'S DISEASE
Author(s) -
Zhang Ming,
Dilliott Allison Ann,
Robinson John,
Hegele Rob,
Comishen Michael,
Sato Christine,
Mayeux Richard,
St George-Hyslop Peter,
Freedman Morris,
Rogaeva Ekaterina
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.817
Subject(s) - epigenetics , offspring , genetics , disease , dna methylation , dementia , biology , cpg site , family history , gene , bioinformatics , medicine , pregnancy , gene expression
mice.Metabolomic analyses indicated changes in lipid andArgmetabolism between females and males within and across the three genotypes. In ApoE3 and ApoE4 females, plasma glycerophospholipid metabolismwas significantly downregulated (p<0.05). Glycerophospholipidswere lowest inApoE3/4 females. In cortex, biogenic amines (a-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.Conclusions:AlloexertedanAPOEgenotype 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 themitochondria. Further, Allo treatment increased indicators of proteinmetabolism. In summary, efficacy ofAllowas evident in both females and males and modified by ApoE genotype. Further therapeutic development of Allo is underway.