Role of Oxysterols in the Activation of the NLRP3 Inflammasome as a Potential Pharmacological Approach in Alzheimer's Disease

Abstract

Alzheimer's disease (AD), the most prevalent form of dementia, is a complex clinical condition with multifactorial origin posing a major burden to health care systems across the world. Even though the pathophysiological mechanisms underlying the disease are still unclear, both central and peripheral inflammation has been implicated in the process. Piling evidence shows that the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in AD. As dyslipidemia is a risk factor for dementia, and cholesterol can also activate the inflammasome, a possible link between lipid levels and the NLRP3 inflammasome has been proposed in Alzheimer's. It is also speculated that not only cholesterol but also its metabolites, the oxysterols, may be involved in AD pathology. In this context, mounting data suggest that NLRP3 inflammasome activity can be modulated by different peripheral nuclear receptors, including liver-X receptors, which present oxysterols as endogenous ligands. In light of this, the current review explores whether the activation of NLRP3 by nuclear receptors, mediated by oxysterols, may also be involved in AD and could serve as a potential pharmacological avenue in dementia.

Keywords: Alzheimer’s disease; LXR; NLRP3 inflammasome; cholesterol; dementia; oxysterols.