Ricerc@Sapienza

The socio-economic burden of aging and related diseases is rapidly increasing, as no treatments are available yet. Several senolytic drugs have been proposed for the treatment of both healthy and pathological aging, as they share some pathological aspects, such as the aberrant myelination. This process is performed by oligodendrocytes in close collaboration with astrocytes. During senescence and pathological conditions, including Alzheimer disease (AD), astrocytes fail to properly support oligodendrocyte precursor cells (OPCs) maturation, leading to a defective myelination. Recently, the well-recognized anti-aging gene klotho has attracted attention for its ability to ameliorate myelination. Klotho is expressed by both neurons and oligodendrocytes, and its expression seems to be improved by peroxisome proliferator-activated receptor (PPAR) agonists. Moreover, it has been proven that PPAR agonists exert important neuroprotective properties. For instance, the PPAR¿ agonist palmitoylethanolamide (PEA) blunts astrocyte reactivity and exerts anti-inflammatory and neuroprotective properties in several AD preclinical models. Moreover, it has been demonstrated that PEA co-ultramicronized with luteolin (co-ultraPEALut) accelerates OPCs maturation. Despite this evidence, no detailed data are available on the molecular mechanisms and the mediators involved in. Aim of this project is to study the effects of co-ultraPEALut on the expression of klotho, correlating its levels to OPCs maturation. Furthermore, to verify whether senescence or astrocyte impairment interfere with OPCs maturation, I will co-culture OPCs with young or aged astrocytes, that will be treated with Aß or vehicle. The ability of co-ultraPEALut to regulate myelination through klotho could represent a new valuable therapeutic approach with rapid translation into clinic, given the well-known safety of PEA.