Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer’s disease by exerting antiinflammatory and neuroprotective effects (original) (raw)

Abstract

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Currenttreatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underliethe decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires amultitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy thatcan be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old)3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Micewere tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magneticresonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potentialneuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chainreaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, andameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβformation,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 restrainsneuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an earlytreatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potentialto be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is alreadyregistered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

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