| Autor: |
Bhattrai, Avnish, McLean, John W., Simmons, Hannah, Raikes, Adam C., Wiegand, Jean‐Paul L., Kaddurah‐Daouk, Rima F., Brinton, Roberta Diaz |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2023 Supplement 14, Vol. 19, p1-2, 2p |
| Abstrakt: |
Background: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for the development of late‐onset Alzheimer's disease (LOAD). Additionally, females have a 2x greater risk of developing LOAD than males. LOAD patients show brain glucose hypometabolism and severe reduction in hippocampal volume. Hippocampal atrophy has also been linked with plasma ceramide and phosphotidylcholine (PC) levels in these patients. This study explores the effects of sex and genotype on the plasma metabolome and potential correlations to brain imaging metrics in an aged humanized APOE (hAPOE) mouse model. Method: Plasma samples from 23–25‐month‐old hAPOE mice (37M/32F) expressing ε3/3, ε3/4 or ε4/4 genotypes were analyzed via mass spectrometry using the Biocrates MxP® Quant 500 platform. In a subset of these animals (24M/20F), in‐vivo FDG‐PET and high‐resolution ex‐vivo MRI were obtained. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum (SUVr). Cerebral SUVr and regional volumes were correlated with detected metabolites and metabolic indicators using Pearson correlations. Two‐way ANOVAs were used to identify sex and genotype effects with post‐hoc t‐tests to determine statistical significance. Result: hAPOE ε3/3 mice had significantly greater cholesteryl ester (54%; p < 0.026) and lysophosphotidylcholine (lysoPC; 27%; p < 0.031) levels compared to ε4/4 mice. Females had lower levels of PCs (93%; p < 0.007), lysoPCs (82%; p < 0.018), triglycerides (62%; p < 0.045), and 1‐Met‐His (p = 5.84E‐25) than males. Significant positive correlations were observed between cerebral SUVr and PCs (45%; p < 0.049) as well as lysoPCs (82%; p <0.017). Total brain volume was negatively correlated with plasma 3‐Met‐His:creatinine ratio, indicative of muscle protein degradation (r = ‐0.44; p = 0.003) and positively correlated with (LysoPC+ arachidonic acid): PC ratio, indicative of phospholipase A2 activity (r = 0.42; p = 0.004). Right hippocampal volume percentage was significantly positively correlated with PCs (64%; p < 0.045) and 1‐Met‐His (p = 0.00067). Conclusion: At a comparable human age of ∼ 70 years, within the humanized APOE mouse, sex was the major contributing factor to metabolic differences in peripheral blood plasma. Levels of peripheral metabolites correlated with brain volumetrics and glucose metabolism, highlighting potential therapeutic targets for interventions designed to preserve neuronal health in AD. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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