title: Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells.
abstract: Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. rosalianalibro@hotmail.it.
authors.forename: Rosaliana
authors.initials: R
authors.lastname: Libro
authors.affiliation: Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti-Pescara, via dei Vestini, 31, 66100 Chieti, Italy. francesca.diomede@unich.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Diomede
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. domenico.scionti@gmail.com.
authors.forename: Domenico
authors.initials: D
authors.lastname: Scionti
authors.affiliation: Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti-Pescara, via dei Vestini, 31, 66100 Chieti, Italy. adriano.piattelli@unich.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Piattelli
authors.affiliation: Council for Research and Experimentation in Agriculture-Research Centre for Industrial Crops (CREA-CIN), 45100 Rovigo, Italy. giampaolo.grassi@gmail.com.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Grassi
authors.affiliation: Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy. federica.pollastro@uniupo.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Pollastro
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. bramanti.dino@gmail.com.
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. emazzon.irccs@gmail.com.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.affiliation: Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti-Pescara, via dei Vestini, 31, 66100 Chieti, Italy. trubiani@unich.it.
authors.forename: Oriana
authors.initials: O
authors.lastname: Trubiani
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D002478:Cells, Cultured; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D016875:tau Proteins; D002185:Cannabidiol; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Alzheimer’s disease; amyloid beta; cannabidiol; glycogen synthase kinase 3β; mesenchymal stem cells; tau