Astrocyte-neuron interplay in Alzheimer's disease: evidence from an innovative and promising pharmacological manipulation in a triple transgenic model of the disease

Background: Alzheimer's disease (AD) is a serious health and economic challenge of the modern age. Current treatments provide only symptomatic relief, making necessary a multitargeted approach against the several pathological processes underlying such disease. In particular, beta-amyloid deposition, tauopathy, astrocyte dysfunction, neuroinflammation and glutamate unbalance recently became promising targets to develop new therapies. In this context, it has been shown that palmitoylethanolamide (PEA) is a multitargeted treatment strategy that provides a novel potential adjunct therapy. Methods: Here, we tested the effects of a 3-months treatment with ultramicronized PEA (um-PEA), a formulation that improves PEA bioavailability, in young (6-month-old) and adult (12-month-old) 3xTg-AD mice, compared to their age-matched Non-Tg mice. Via a subcutaneous delivery system, the treatment mimicked the clinic use with a chronic daily administration. At the end of the treatments, potential neuropathological mechanisms were assessed by western blot, reverse transcription - polymerase chain reaction (RT-PCR), and immunofluorescence in the hippocampal tissues. Results: Our finding revealed that um-PEA normalizes astrocytic functionality, rebalances the astrocyte glutamate regulating system, reduces Aβ formation and tau hyperphosphorylation, restrains neuroinflammation and promotes neuronal survival in 3xTg-AD mice. Interestingly, PEA effects where more pronounced in young mice suggesting its potential as an early treatment. Conclusions: um-PEA is a novel potential treatment whose multitargeted efficacy is powerful especially in early and asymptomatic phases of AD, suggesting its application as a precocious approach. Since PEA is already licenced for use in humans, displaying a high tolerability and safety profile, it would be an ideal candidate for a long-term use lasting several years, as potential AD treatment requires.