UNVEILING THE COMPLEX ROLE OF NF-ΚB IN ALZHEIMER'S DISEASE: INSIGHTS INTO BRAIN INFLAMMATION AND POTENTIAL THERAPEUTIC TARGETS

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and dementia. One of thae major pathologies underlying AD is chronic neuroinflammation mediated by microglia and astrocytes in the brain. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway is a key regulator of inflammation and has been implicated in the neuroinflammatory processes associated with AD. This review comprehensively summarizes current findings on the complex role of NF-κB signalling in AD pathogenesis. The canonical and non-canonical NF-κB activation pathways are described, along with evidence from human studies and animal models demonstrating increased NF-κB activity in AD brains. The deleterious effects of NF-κB-mediated neuroinflammation are discussed, including the upregulation of inflammatory cytokines, chemokines, and enzymes that exacerbate neuronal damage over time. Targeting the NF-κB pathway is proposed as a promising therapeutic approach to dampen neuroinflammation in AD. Preclinical studies utilizing genetic or pharmacological inhibition of NF-κB are reviewed, and key challenges in translating these findings to clinical applications are analyzed. Overall, this review unveils the multifaceted contributions of NF-κB signalling to AD neuropathology and highlights anti-neuroinflammatory NF-κB modulation as a potential avenue for future AD treatments. Further research is warranted to fully elucidate the complex interactions between NF-κB and AD pathogenesis.

Keywords: Alzheimer’s disease; NF-κB; Microglia; neurodegeneration; neuro-inflammation.