Ultramicronized palmitoylethanolamide improves learning and memory in a triple transgenic mouse model of Alzheimer's disease through a combination of anti-inflammatory and neuroprotective effects

Alzheimer's disease (AD) is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young and adult 3×Tg-AD mice that received ultramicronized PEA (um-PEA, a formulation endowed with best bioavailability) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and non-cognitive tasks, and potential neuropathological mechanisms were assessed post-mortem by western blot, RT-PCR, and immunofluorescence. Our data demonstrate that um-PEA rescues behavioral impairments and reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs.