Docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the brain,
is essential for successful aging. In fact, epidemiological studies have demonstrated that increased
intake of DHA might lower the risk for developing Alzheimer’s disease (AD). These observations
are supported by studies in animal models showing that DHA reduces synaptic pathology and
memory deficits. Different mechanisms to explain these beneficial effects have been proposed;
however, the molecular pathways involved are still unknown. In this study, to unravel the main
underlying molecular mechanisms activated upon DHA treatment, the effect of a high dose of DHA
on cognitive function and AD pathology was analyzed in aged Tg2576 mice and their wild-type
littermates. Transcriptomic analysis of mice hippocampi using RNA sequencing was subsequently
performed. Our results revealed that, through an amyloid-independent mechanism, DHA enhanced
memory function and increased synapse formation only in the Tg2576 mice. Likewise, the IPA
analysis demonstrated that essential neuronal functions related to synaptogenesis, neuritogenesis, the
branching of neurites, the density of dendritic spines and the outgrowth of axons were upregulated
upon-DHA treatment in Tg2576 mice. Our results suggest that memory function in APP mice
is influenced by DHA intake; therefore, a high dose of daily DHA should be tested as a dietary
supplement for AD dementia prevention.
