Long-term administration of ultra-micronized PEA alters disease progression in the Tg2576 mice and reveals neuroprotective effects on behavior, brain morphology and biochemistry.

Alzheimer's disease (AD) is the most common cause of dementia and yet, effective pharmacological therapies are missing. Neuroinflammation plays a crucial role in AD progression, prompting research into the modulation of the immune system as an innovative therapeutic strategy. Thus, identification of novel targets restraining neuroinflammation is crucial to prevent or delay disease progression. Palmitoylethanolamide (PEA) is an emerging nutraceutical compound with high efficacy/risk ratio and lack of tolerance induction and interference with other pharmacological therapies. PEA is an endogenous N-acylethanolamine that acts as bioactive lipid mediator, and is biochemically and functionally related to the endocannabinoid system. PEA is produced by neurons, microglia and astrocytes in responses to various damaging processes, with an overall pro homeostatic role. Preclinical studies showed the anti-inflammatory, pain-relieving, and neuroprotective actions of ultra-micronized (um) PEA, a formulation that favors its bioavailability. The present study aims at evaluating the neuroprotective potential of chronic umPEA treatment via 6-month subcutaneous pellets on learning, memory and motivation (by Novel Object Recognition Test and Conditioned Place Preference), synaptic plasticity, neuroinflammation, and oxidative stress in 12-month-old Tg2576 (Tg) mice (from 6 to 12 months of age), a widely used AD mouse model. Chronic PEA treatment was able to prevent cognitive impairment and preserve motivation. Moreover, PEA protected hippocampal CA1 pyramidal neurons from spine density decrease in apical and basal dendrites. Neuroinflammatory astrogliosis was alleviated by PEA treatment by reducing GFAP levels in cortex and hippocampus. Furthermore, PEA prevented the transition of hippocampal microglial cells to a hyper-reactive phenotype, characterized by the extension and hyperramification of processes. Consistently, significant changes were observed in the hippocampal cytokine profile of PEA-treated Tg mice, exhibiting a reduction of cytokines responsible for recruiting immune system cells and triggering the neuroinflammatory response. PEA treatment was also able to modulate oxidative stress in Tg mice reducing significantly 3-nitrotyrosine levels in plasma, cortex and hippocampus, and reducing inducible nitric oxide synthase levels in cortex and hippocampus. These results demonstrate PEA neuroprotective and anti-inflammatory effects and its therapeutic potential in the early phases of AD pathology. PEA, as a modifier of the disease progression, might enhance the quality of life in the elderly and promote healthy ageing.