Professor University of Sherbrooke Sherbrooke, Quebec, Canada
Introduction/Rationale: There is growing evidence supporting the potential role of microbial infections in the aetiology of Alzheimer’s disease (AD). We aim to evaluate the effect of raltegravir, either alone as a single therapy or combined with elacridar, a P-gp/BCRP inhibitor, on AD-related pathways in vitro.
Methods: Flow cytometry combined was used to quantify the expression of key inflammatory markers, including interleukin-1β (IL-1β), NLRP3 inflammasome components, costimulatory molecules (CD86), and the class B scavenger receptor (SR-B2) CD163, in HMC3 human microglia cells. Furthermore, the effect of raltegravir on Aβ1-42-induced p-tau 181 expression in H4 human neuroglioma cells was assessed.
Results: Results. Our data indicate that raltegravir significantly (p < 0.01) abolishes the Aβ1-42-stimulating effect on p-tau 181, and that this effect involves the downregulation of PP2Aα+β. The observed reduction of p-tau 181 by raltegravir is potentially mediated by the inhibition of tau-phosphatases. Aβ1-42 significantly upregulated the expression of the surface receptors CD86 and CD163 in HMC3 microglial cells. Raltegravir treatment significantly reduced CD86 expression, while it had no significant effect on Aβ1-42-induced CD163 expression (p>0.05). Further,raltegravir significantly (p < 0.05) attenuated IL-1β cytokine release, likely via downregulation of NLRP3-inflammasome signalling pathway in microglia.
Conclusion: Taken together, our findings suggest that raltegravir exerts a neuroprotective effect by targeting pathological events associated with AD, particularly tau phosphorylation and neuroinflammation.
