n-3 Polyunsaturated fatty acids substitution for saturated fatty acids in diet ameliorates age-related cognitive decline via ABCA1/ApoE-mediated lipid efflux

Dietary lipids are essential for brain health. However, high-fat diets (HFD) have produced conflicting results in studies on aging brain health, likely due to variations in fatty acid composition. While aging-related glial lipid accumulation is exacerbated by saturated fatty acids (SFAs)-rich HFD, it remains unclear whether replacing SFAs with n-3 polyunsaturated fatty acids (PUFAs) can mitigate this effect and the associated neuroinflammation. This study investigates the effects of SFAs-rich and n-3 PUFAs-rich HFDs in 18-month-old C57BL/6J mice over a 12-week period. Mice fed the SFAs-rich HFD showed increased body weight, elevated glucose and lipid levels, and lipid accumulation in glial cells. Behavioral tests, including novel object recognition and the Barnes maze, revealed significant cognitive impairments in these mice. In contrast, the n-3 PUFAs-rich HFD increased brain docosahexaenoic acid levels, activated the ATP-binding cassette transporter A1/apolipoprotein E pathway, reduced lipid accumulation in glial cells, and ultimately reversed cognitive decline. Consistent with these findings, the n-3 PUFAs-rich diet also attenuated inflammatory markers such as tumor necrosis factor α and interleukin 1β, and decreased oxidative stress markers including malondialdehyde and oxidized glutathione/reduced glutathione. These findings provide novel insights into the role of fatty acid composition in HFD affecting aged brain health, offering strong evidence for the neuroprotective benefits of n-3 PUFAs-enriched diets.