Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer’s Disease Pathogenesis in a Transgenic Mouse Model

Autor: Santiago Rivera, Max de Reggi, Wassila Carpentier, Delphine Stephan, Kévin Baranger, Bouchra Gharib, Manuel van Gijsel-Bonnello, Michel Khrestchatisky, Philippe Benech
Přispěvatelé: Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Dundee, UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Neurotherapeutics
Neurotherapeutics, 2019, ⟨10.1007/s13311-019-00754-z⟩
Neurotherapeutics, Springer Verlag, 2019, ⟨10.1007/s13311-019-00754-z⟩
ISSN: 1933-7213
DOI: 10.1007/s13311-019-00754-z⟩
Popis: The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-β (Aβ)-induced IL-1β release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer’s disease (AD).1.5-month-old Tg and wild-type (WT) male mice were submitted to intraperitoneal administration of pantethine or saline control solution for 5.5 months. The effects of such treatments were investigated by performing behavioral tests and evaluating astrogliosis, microgliosis, Αβ deposition, and whole genome expression arrays, using RNAs extracted from the mice hippocampi. We observed that long-term pantethine treatment significantly reduced glial reactivity and Αβ deposition, and abrogated behavioral alteration in Tg mice. Moreover, the transcriptomic profiles revealed that after pantethine treatment, the expression of genes differentially expressed in Tg mice, and in particular those known to be related to AD, were significantly alleviated. Most of the genes overexpressed in Tg compared to WT were involved in inflammation, complement activation, and phagocytosis and were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of Αβ processing and synaptic activities, which were downregulated in Tg mice. Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by Aβ pathogenesis in Tg mice and highlight the potential efficiency of pantethine to alleviate AD pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00754-z) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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