This study investigated effects of docosahexaenoic acid (DHA) on synaptic plasticity in Tg2576 mice. Epidemiological studies suggest that people who ingest higher levels of DHA are less likely to develop AD dementia. The reasons for the impact of DHA on learning and memory and the association with AD have been unclear but could result from its loss in synapses. Moreover, memory loss correlates better with synapse loss than with plaques or tangles. This study reported that reduction of dietary n-3 PFA in Tg2576 mice resulted in 80%– 90% losses of the p85α subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. N-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for AD.