Neuronal Count, Brain Injury, and Sustained Cognitive Function in 5×FAD Alzheimer’s Disease Mice Fed DHA-Enriched Diets

Alzheimer's disease (AD) is the most common form of dementia, affecting over 50 million people globally. Since 1906, efforts to understand this neurodegenerative disease and to develop effective treatments have continued to this day. Recognizing docosahexaenoic acid (DHA, 22:6n-3) as a safe, inexpensive and vital nutrient for brain health and cognitive protection due to its key role in brain development and function, this study explores novel, sustainable non-fish sources as potential dietary supplements to prevent or mitigate AD, within a blue biotechnology framework. Forty 5×FAD male mice, five weeks old, were allocated to five body weight-matched dietary groups (<i>n</i> = 8) and fed isocaloric diets based on AIN-93M standard chow for 6 months. Each diet, except the control feed (non-supplemented group), enclosed a modified lipid fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA,18:3n-3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n-3)); (3) <i>Schizochytrium</i> sp. microalga oil (Schizo) with 40% of DHA; and (4) commercial DHASCO oil (DHASCO) with 70% of DHA. The different diets did not affect (<i>p</i> > 0.05) growth performance criteria (e.g., final body weight, daily feed intake, and body weight gain) suggesting no effect on the overall caloric balance or mice growth, but n-3 long-chain polyunsaturated-fatty acid (n-3 LCPUFA) supplementation significantly reduced total cholesterol (<i>p</i> < 0.001) and total lipids (<i>p</i> < 0.001). No systemic inflammation was detected in 5×FAD mice. In parallel, a beneficial modulation of lipid metabolism by DHA-enriched diets was observed, with polyunsaturated fatty acid incorporation, particularly DHA, across key metabolic tissues, such as the liver (<i>p</i> < 0.001) and the brain (<i>p</i> < 0.001). No behavioural variations were detected using an open-field test after 6 months of diet (<i>p</i> > 0.05). While mice fed a standard diet or LSO diet showed cognitive deficit, the incorporation of FO, Schizo or DHASCO oils into dietary routine showed promising protective effects on the working memory (<i>p</i> < 0.05) and the last two diets also on the recognition memory (<i>p</i> < 0.05) Increased neuronal count (<i>p</i> < 0.05), reflecting neuronal survival, was clearly observed with the fish oil diet. In turn, the number of TAU-positive cells (<i>p</i> < 0.05) was reduced in the Schizo diet, while β-amyloid deposition (<i>p</i> < 0.01) and the neuroinflammatory marker, IBA1 (<i>p</i> < 0.05), were decreased across all DHA-enriched diets. These promising findings open new avenues for further studies focused on the protective effects of DHA derived from sustainable and underexploited <i>Schizochytrium</i> sp. microalga in the prevention of AD.