Palmitoylethanolamide controls astrocyte activation and the amyloidogenic pathway in an in vivo model of Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most diffuse type of dementia characterized not only by senile plaques and neurofibrillary tangles, but even by a glial activation and a chronic inflammatory status called “reactive gliosis”. Nowadays it is well recognized that this phenomenon participates actively to neurodegeneration. Several markers can be used to characterize reactive gliosis; among them S100B represents one of the most important. This neurotrophin becomes toxic during brain injuries, ischemia and several neurological disorders, including AD. Indeed, it has been established that S100B plays a pivotal role in the amyloidogenic pathway of β-amyloid (Aβ). In fact this molecule is able to increase the Aβ precursor protein and the β-secretase activity, by rising the Aβ levels which, in turn, further activate astrocytes. This self-sustaining loop drives the progression of pathology. Pharmacological manipulation of this detrimental loop could be useful to develop new therapies. In this context, palmitoylethanolamide (PEA), an endogenous lipid compound, exerts many pharmacological activities, especially a marked anti-inflammatory action in peripheral inflammatory models. For this reason we decided to test PEA activity in an in vivo model of AD. Obtained results demonstrated that PEA is able to counteract astrocyte activation as well as reduce pro-amyloidogenic pathway through a mechanism partially peroxisome proliferator-activated receptor-α-depending.