Effects of palmitoylethanolamide on the onset and progression of the pathology on a triple transgene mouse model of Alzheimer disease.

Alzheimer disease (AD) is the most common form of neurodegenerative dementias where the major pathogenic mechanisms remain to be clarified. Data from animal models and human autopsy revealed that reactive gliosis might exert a key pathogenetic role in AD. It is reasonable to assume that 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 amide of ethanolamine and palmitic acid, abundant in the CNS, and produced by glial cells, studied for its anti-inflammatory and neuroprotective effects. In the present work we exploited the availability of a transgenic model of AD (3xTg-AD) harboring three mutant human genes (betaAPPSwe, PS1M146V, tauP301L) to investigate if chronic PEA treatment might modulate the onset and the progression of Abeta and tau pathologies. The 3xTg-AD mice develop amyloid plaques and neurofibrillary pathology in AD-relevant brain regions (Hip, cortex) and mimic the disease progression in humans. An integrated approach, involving in vivo MRS and histological studies were used. The experimental strategy involved a longitudinal ageing study examining metabolic alteration and relating any changes with indices of brain pathology taken from a subset of mice killed at 6 and 12 months of age. The experiment compared 3xTg-AD mice at 6 (n=11) and 12 (n=16) months of age and wildtype controls (n=13 and n=14, for 6 and 12 months, respectively). Animals were treated with chronic PEA administration and then undergo MRI and MRS scanning (VARIAN Inova MRI/MRS system, 4.7T) to evaluate genotype- and treatment- induced differences in brain metabolism. Parallel RT-PCR and Western blot analyses have been also performed. Quantitative MRS analyses indicate that PEA treatment affects brain metabolism. Our findings are supported by parallel RT-PCR and Western blot analyses. The current investigation provides evidence that PEA rescues altered molecular pathways that can mimic some traits of AD. Considering the safety and tolerability of PEA in humans, our findings offer new opportunity in AD treatment.