I021 Treatment with the sphingolipid modulator THI, preserves hippocampal homeostasis and mitigates cognitive deficit in a HD mouse model

<h3>Background</h3> A number of evidence, demonstrates that defective (glyco)sphingolipid pathways may contribute to the pathogenesis of Huntington’s disease (HD). In particular, aberrant metabolism/levels of both simple (Sphingosine-1-Phosphate - S1P -) and complex (Glucosylceramide and Gangliosides) sphingolipids has been reported in both HD pre-clinical models and human post-mortem brains from patients. <h3>Aim</h3> In this study, we investigate the ability of THI, an inhibitor of S1P degradative enzyme SGPL1, in counteracting cognitive dysfunctions in HD mice. <h3>Methods</h3> Both WT and R6/2 mice were treated with either vehicle or THI (0.1mg/kg) for five weeks. Cognitive deficits were assessed by Novel Object Recognition test and Y-Maze Test. Western Blot and qPCR analyses were performed to assess protein and gene expression profiles, respectively. <h3>Results</h3> THI treatment mitigated mouse cognitive deficit modulated (glyco)sphingolipid pathways and preserved hippocampal homeostasis. The compound also stimulated the autophagic flux and the endo-lysosome system, facilitating the reduction of mutant huntingtin aggregates. <h3>Conclusion</h3> This study confirmed the ability of THI to counteract the disease phenotypes observed in HD mice, and further support the notion that the modulation of (glyco)sphingolipid homeostasis may represent and effective therapeutic option for the disease.