Antiretroviral raltegravir, a selective human immunodeficiency virus type 1 integrase inhibitor, shows anti-Alzheimer's potential against amyloid-beta_1-42-induced neurodegeneration.

There is growing evidence supporting the potential role of microbial infections in the aetiology of Alzheimer's disease (AD) and the protective role of anti-viral therapies. However, not much is known about the molecular mechanisms underlying their effects. We aimed to explore the modulatory role of raltegravir on monomeric amyloid beta 1-42 (m-Aβ_1-42)-induced molecular alterations in cellular models of AD. Here we show, using the flow cytometry technique combined with specific monoclonal antibodies, that raltegravir significantly abolishes the m-Aβ_1-42-stimulating effect on p-tau 181, and that this effect involves the upregulation of PP2Aα+ β. This effect does not appear to be mediated by GSK-3β and CdK5 modulation, since no significant effect was observed on these kinases. Furthermore, raltegravir treatment significantly reduced CD86 expression without any impact on CD163, suggesting a possible affinity towards reducing the microglia M1-phenotype rather than improving the M2 state. Additionally, raltegravir significantly attenuated IL-1β production, likely through the downregulation of the NLRP3-inflammasome signaling pathway, indicating an important anti-inflammatory activity. Collectively, our in vitro findings are preliminary mechanistic observations that support raltegravir's repurposing for AD, thus soliciting further complementary research, especially in relevant animal models of AD, to accelerate the translation of these findings into the clinical setting.