Targeting the NLRP3 inflammasome pathway associated with neuroinflammation mediated Alzheimer’s disease: pre-clinical and clinical status of emerging therapeutics

Abstract

ABSTRACT Introducion Alzheimer’s disease (AD) is a rising global health problem, but current treatments only target symptoms rather than fixing their underlying root causes. A major pathological feature is neuroinflammation, which is specifically driven by the Nucleotide-binding domain, Leucine-rich-repeat and Pyrin domain-containing 3 (NLRP3) inflammasome cascade, which acts as a ‘molecular switch’ that causes immune cells in the brain to trigger robust secretion of pro-inflammatory cytokines (e.g. IL-1β, IL-18) and pyroptosis, causing systemic inflammation, consequently, neuroinflammation. Areas covered This review breaks down the pathways triggered by immune cells activation (neurotoxic microglial phenotype) and mainly focuses on the NLRP3 inflammasome neuroinflammation pathway. It explores the promising therapeutic potential of specific bioactive phytochemicals, repurposed and novel synthetic drugs/agents, to shut-down this molecular switch, i.e. NLRP3 inflammasome pathway. Expert opinion To truly stop AD, we must shift our focus from treating merely the symptoms, by stopping the disease at its roots. While discovering the novel NLRP3 inflammasome inhibitors is exciting, the biggest hurdle is getting them into the brain. The future of AD treatment relies on combining these targeted drugs with advanced nanotechnology, like nano-particles, to successfully cross the blood-brain barrier (BBB) and safely deliver the drugs exactly where they are needed. PLAIN LANGUAGE SUMMARY Alzheimer’s disease (AD) is a growing global health issue, but current treatments only manage symptoms without addressing the underlying root causes. A key factor in AD is neuroinflammation, a process in which the brain’s immune cells trigger chronic inflammation. This inflammatory process is largely driven by a specific ‘molecular switch’ known as the NLRP3 inflammasome. This article reviews new and existing medicines, including natural plant-based compounds and synthetic drugs, that are being screened to turn-off this molecular switch. By directly blocking the NLRP3 inflammasome, these treatments aim to stop the disease at its source. However, a major challenge arises in getting these drugs into the brain, which highlights the need to combine these targeted drugs/phytochemicals with advanced delivery methods, such as nanoparticles, to safely and effectively reach the affected areas.