Hippocampal metabolic and behavioural improvements after palmitoylethanolamide treatment at early stage of development in a triple transgene mouse model of Alzheimer disease.

INTRODUCTION Alzheimer disease (AD) is the most common form of dementias in aging humans. Reactive gliosis might exert a pathogenetic role in AD. Early combination of neuroprotective and anti-inflammatory treatments aimed at restoring astrocyte functions may represent an appropriate approach to treat AD. PEA (palmitoylethanolamide) is a naturally occurring compound produced by glial cells. The anti-inflammatory and neuroprotective effects of PEA as well as its ability to attenuate memory impairment in rodent models of AD have been recently shown (Scuderi et al, 2014, Tomasini et al, 2015). AIMS of this work were to investigate the effect of PEA treatment in 3xTg-AD mice (betaAPPSwe, PS1M146V, tauP301L mutant genes) at two different stages (mild and severe) of AD-like pathology. METHODS Adult 3xTg-AD mice (of 3 and 9 month of age) were chronically treated for 3 months with ultramicronized-PEA (um-PEA) and evaluated in a battery of behavioral tests focused on AD symptomatology. Then, animals undergo MRI and MRS (VARIAN Inova 4.7 T) to evaluate genotype- and treatment- induced differences in hippocampus metabolism according with a quantitative protocol (Canese et al, 2012). RESULTS and DISCUSSION MRI/MRS analyses revealed a reduction of both glutamate (Glu) and N-acetylaspartate (NAA) content in the Hip of 6-month-old 3Tg-AD mice compared to Non-Tg animals. Such results are in agreement with AD-patient finding (Rupsingh et al, Neurobiol Aging. 2011) and may explain the important cognitive deficits observed at this age. Um-PEA treatment increased Glx content in transgenic animals and reduced the behavioural abnormalities observed in the 3Tg-AD mice. Also in the Hip pf AD patients, a Glu increase which could be associated with increased cognitive performance after anti-inflammatory treatment (Penner et al, Prog Neuro-Psychopharmacol Biol Psychiatry. 2010). CONCLUSION Our results provide evidence of the behavioral and molecular modifications occurring during AD development, and highlight the therapeutic potential of um-PEA in controlling disease.