Reactive astrogliosis and neuronal impairment: in vitro and in vivo evidence on palmitoylethanolamide effects in a triple transgenic model of Alzheimer’s disease

More than 60-80% of dementia cases worldwide in elderly people is caused by Alzheimer’s disease (AD) (Alzheimer’s disease Facts and Figures, 2017). Histopathologically, AD is characterized by the aggregation of extracellular neuritic β-amyloid peptide that leads to the creation of senile plaques, and the production of intracellular neurofibrillary tangles caused by tau protein hyperphosphorylation (Braak et al., 1988; Merz et al., 1983). Recently, abnormally activated glial cells, previously considered only space-filling and supporting cells of the central nervous system, were recognized as another crucial feature of AD brains (Rodriguez et al., 2009). This phenomenon, accompanied by an intense inflammation, is defined reactive astrogliosis (Verkhratsky et al., 2010; 2012). Physiologically, it has a defensive intent aimed at removing injurious stimuli, but if prolonged and unstopped, as in the case of AD, it causes neuronal dysfunction and death (Brown et al., 2003). Considering these evidence, an early combination of neuroprotective and anti-inflammatory treatments may represent an efficacious approach to counteract AD. In this context, palmitoylethanolamide (PEA), an endogenous lipid mediator, already tested in a surgical model of AD (Scuderi et al., 2011; 2014; Tomasini et al., 2015), is an excellent candidate. We investigated the presence of reactive astrogliosis in a triple transgenic model of AD (3×Tg-AD) and the effects of PEA by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3xTg-AD-derived astrocytes and the ability of PEA in counteracting this phenomenon. PEA also improved the viability of 3xTg-AD-derived primary neurons. In vivo experiments, conducted using ultramicronized-PEA, a formulation that improves its bioavailability, revealed the efficacy of this compound in dampening reactive astrogliosis and promoting the glial neurosupportive function. Considering that the safety and efficacy of PEA have been already proven also in human (Nestmann et al., 2017), our results impel towards a possible translation of these data into the clinical practice.