Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• The apolipoprotein E (APOE) 4 genotype is a significant genetic risk factor for Alzheimer disease (AD).
• Female APOE4 carriers exhibit a higher risk for AD compared to males.
• Age-related changes in brain lipid profiles and specialized proresolving mediators (SPMs) may influence AD pathology.

Purpose of the Study:

• To investigate the impact of APOE genotype and sex on brain fatty acid, phospholipid, and SPM profiles in aging mice.
• To determine age-associated alterations in docosahexaenoic acid (DHA) and its metabolites in APOE3 and APOE4 mice.
• To explore potential sex-specific differences in brain lipid metabolism related to AD risk.

Main Methods:

• Quantification of cortical and hippocampal fatty acid and phospholipid profiles in 2-, 9-, and 18-month-old male and female mice with APOE3 and APOE4 genotypes.
• Measurement of select eicosapentaenoic acid (EPA)- and DHA-derived SPMs.
• Comparative analysis of lipid and SPM levels based on age, sex, and APOE genotype.

Main Results:

• A significant decrease in cortical DHA was observed in 18-month-old APOE4 female mice compared to younger counterparts, linked to reduced DHA-phosphatidylethanolamine.
• Older APOE4 females showed a 15% increase in oleic acid compared to young mice.
• While SPM ratios were not sex*genotype dependent, females generally had higher levels of certain DHA-derived SPMs, whereas APOE4 mice showed lower levels of specific SPMs like resolvin D1.

Conclusions:

• An association exists between aging, female sex, and the APOE4 genotype, characterized by decreased cortical DHA and altered SPM profiles.
• These neurochemical changes in APOE4 female mice may contribute to cognitive decline and Alzheimer disease pathology.
• The findings highlight the complex interplay of genetics, sex, and aging in brain lipid metabolism and AD pathogenesis.