New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer's Disease and Its Potential for Therapeutic Intervention

Abstract

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

Keywords: Alzheimer’s disease; NF-κB; NLRP3; TREM2; cGAS-STING; neuroinflammation.

Figure 1

Schematic illustration indicates the role of the microglial NF-κB, NLRP3, TREM2, and cGAS-STING in Alzheimer’s disease. Aβ triggers the activation of the NF-κB pathway and NLRP3 inflammasome, leading to inflammatory cytokine release and promoting the pyroptotic death of neurons. TREM2 pairs with DAP12 through charge interactions in the transmembrane domain. Aβ and lipid proteins are the main binding ligands on the TREM2 receptor. Upon binding, DAP12 gets phosphorylated and recruits spleen tyrosine kinase (SYK), which initiates a cascade of signaling events, including phosphoinositide 3-kinase (PI3K) activation, that targets AKT and then activates mammalian target of rapamycin (mTOR), leading to inhibition of autophagy and degradation of Aβ. Foreign or mt DNA activates cGAS, which synthesizes the second messenger cGAMP from ATP and GTP. cGAMP binds to STING, leading to downstream activation of transcription factors for type I IFNs and proinflammatory cytokines that modulate neuroinflammation to produce an immune response against the pathogenic entity.