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

Abstract

Background: 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- (A)-induced IL-1 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). Methods: 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,  deposition and whole genome expression arrays, using RNAs extracted from the mice hippocampi. Results: We observed that long-term pantethine treatment significantly reduced glial reactivity and  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, were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of  processing and synaptic activities, which were down-regulated in Tg mice. Conclusions: Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by A pathogenesis in Tg mice, and highlight the potential efficiency of pantethine to alleviate AD pathology.

Quantitative Brain Positron Emission Tomography in Female 5XFAD Alzheimer Mice: Pathological Features and Sex-Specific Alterations

“…However, we decided to focus on 7-month-old mice as female 5XFAD mice show a robust Abeta pathology as well as severe memory deficits at this age. Furthermore, this age is often used as an endpoint in treatment studies in 5XFAD mice (66)(67)(68)(69)(70)(71). Thus, our present findings underline that PET imaging with 18 F-FDG-and 18 F-Florbetaben could provide a valuable and robust preclinical evaluation tool of therapeutic strategies modulating the AD pathology in 5XFAD mice.…”

Advances in Therapeutic Applications of Extracellular Vesicles

“…Pantethine affects the membrane lipid bilayer recombination process in MV formation by reducing lipid metabolism and total cholesterol levels, which inhibits the release of MV from the membrane. 94 , 95 For example, in the brain syndrome model of Plasmodium bergi Anka-infected mice, the disulfur group in the molecular structure of pantethine inhibits EV release from infected cells, thus preventing the occurrence of cerebral malaria. 96 GW4869 is a dihydroimidazolamide compound that affects lipid metabolism, and can be used as a non-competitive inhibitor of membrane lipid neutral sphingomyelinase (nSMase) to indirectly inhibit exosome release.…”

The vitamin B5/coenzyme A axis: A target for immunomodulation?

“…Therefore, pantethine supplementation experiments were tested in various models of neurodegenerative diseases and generally led to an improvement of the pathology. In a transgenic Alzheimer's disease's model, it reduced the symptoms of glial reactivity, amyloid‐β deposition, and inflammation [75], and in a Parkinson disease's model, it correlated with the enhanced production of ketone bodies, a process dependent on l ‐3‐hydroxybutyryl‐CoA dehydrogenase activity [76]. Interestingly, the aminothiol cysteamine also exerted a cytoprotective effect in Parkinson [77] and Huntington disease's [78] models, through the modulation of redox metabolism and detoxication pathways [79].…”