Title : S1PR-1 as a new target for the treatment of Tau-related pathologies?
Background: Tau proteins are known to help maintaining the structure of a neuron, including tiny tube-like structures called microtubules, which deliver nutrients throughout cells. However, when hyperphosphorylated, these proteins can become toxic for neurons by forming tangles in the hippocampus; one important region of the brain early affected by Alzheimer’s disease. Researchers believe that therapies capable to limit Tau phosphorylation in the hippocampus may reduce tangle formation and ultimately intervene in the development of Alzheimer’s disease and other Tau-related disorders. Global sphingosine-1- phosphate receptor (S1PR) agonists were recently found to exert neuroprotective effects in several model systems reproducing different brain disorders. Consequently, we assessed the influence of such compounds on Tau phosphorylation in the hippocampus.
Methods and Results: Transverse rat hippocampal slices were prepared with a McIlwain tissue chopper and placed on a nylon mesh in a liquid-gas interface chamber. They were treated for a period of 3 hours with S1PR-1 (SEW2871) and S1PR3 (CYM5541) agonists. Tau phosphorylation was then estimated by Western blotting procedures.We noticed an important reduction in Tau-Ser262 phosphorylation after hippocampal slice treatments with the S1PR-1 agonist SEW2871. In terms of molecular mechanisms, SEW2871-induced Tau-Ser262 dephosphorylation seems to be dependent on AMPK (AMP-activated protein kinase) inactivation, a process involving the protein phosphatase PP2A. Comparable experiments indicate that neither Tau nor AMPK were influenced by the S1PR-3 agonist CYM5541 (data not shown). Our results suggest a new target for Tau dephosphorylation and provide an insight into the potential therapeutic effects of S1PR agonists in Alzheimer’s disease and other Tau-related pathologies.
Acknowledgements: This work was supported by the Canadian Research Chair in Molecular Neuropharmacology (Michel Cyr) and by the National Sciences and Engineering Council of Canada (Guy Massicotte).
Highlights of this presentation: Tau-related pathologies are extremely common in the central nervous of patients suffering with Alzheimer’s disease. For many scientists, avoiding brain cells from developing hyperphosphorylated Tau could eventually prevent Alzheimer’s from robbing people of their minds. On that line, Guy Massicotte has identified a new compound that may be able to reduce Tau phosphorylation in the brain. The molecular target might be the receptor subtype 1 for the ceramide derivative sphingosine-1-phosphate (S1P). Guy Massicotte and his colleagues are currently testing with various drugs how this receptor complex might reduce inflammation and protect the brain from Tau-related insults.