Targeting RIPK1-NF-κB crosstalk: A novel perspective on necroptosis in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterised by gradual neuronal degradation, resulting in cognitive decline and memory loss. Multiple pathogenic mechanisms drive the progression of the disease, including amyloid-β (Aβ) and tau accumulation (neurofibrillary tangles), mitochondrial dysfunction, synaptic loss, chronic neuroinflammation, and neuro​nal death. Neuronal loss in AD occurs through various forms of regulated cell death, including apoptosis, ferroptosis, pyroptosis, parthanatos, and necroptosis, each characterised by specific pathways and subsequent inflammatory consequences. Despite decades of focus on apoptosis and necrosis as the primary modes of neuronal loss, necroptosis has remained relatively understudied until recently. Necroptosis is a caspase-independent, inflammatory cell death pathway governed by the RIPK1-RIPK3-MLKL signalling axis. Activation of this pathway disrupts plasma membrane integrity, triggering the release of damage-associated molecular patterns (DAMPs) that sustain a self-propagating cycle of neuroinflammation and secondary neuronal loss. Crucially, RIPK1 signalling is closely linked to nuclear factor-[Formula: see text]B (NF-[Formula: see text]B), a principal modulator of inflammatory and cell-survival mechanisms. Although NF-[Formula: see text]B activation can facilitate neuronal survival under physiological conditions, its sustained activation in the AD brain promotes the synthesis of pro-inflammatory mediators, thereby accelerating neurodegeneration. This review discusses the emerging role of RIPK1-mediated necroptosis in AD and examines its functional interaction with NF-[Formula: see text]B signalling in driving neuroinflammation. Additionally, it examines emerging therapeutic strategies targeting the RIPK1-NF-[Formula: see text]B axis to alter disease progression and achieve disease-modifying potential in AD.