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.
Since the number of the world¿s population aged > 60 years will double in the next four decades (PMID: 25323246), an increased incidence of age-related diseases is expected. Several data support the view that astrocyte senescence importantly contribute to age-related disease pathogenesis, including AD. Therefore, researchers are looking for senolytic agents against aged astrocytes as a possible treatment for these pathologies (PMID: 32508595). Glial cells represent key players in AD pathogenesis. Despite great scientific efforts, the role of these cells has not been completely characterized. For instance, little is known about astrocyte-oligodendrocyte coupling alteration in both aging and AD. This project intends to characterize in vitro the major features of the astrocyte-oligodendrocyte coupling aimed at myelination, hypothesizing a possible mechanism of action and testing the effects of a valuable pharmacological treatment.
Great interest is growing around klotho properties as an anti-aging gene and as a myelination enhancer. To this regard, literature offers a clear ground of investigation, for which the connection among PPARs, klotho and myelination appears promising. My working hypothesis is that activation of the astrocyte PPAR¿ by co-ultraPEALut enhances the levels of klotho in co-cultured OPCs, thus promoting maturation of these cells to myelinating oligodendrocytes. My group of research and I have a long experience with glial cell cultures as well as with PEA effects on these cells, as demonstrated by different publications (PMIDs: 21255263-22405189-25210802-29576849-29382825-32471239). Moreover, co-ultraPEALut has already been approved for human use, making it quickly exploitable in the clinical practice. A possible ability of this compound to ameliorate astrocyte support to OPCs during physiological and pathological aging by modulating klotho levels will result in a rescued myelinization of the CNS. Therefore, these findings could be also relevant for the treatment of several demyelinating disorders.