Neuromodulatory Roles of Necroptotic Pathways in Alzheimer’s Disease: Mechanistic Insights and Therapeutic Prospects

Abstract

Alzheimer’s disease (AD) involves progressive cognitive decline driven by interconnected mechanisms of protein aggregation, neuroinflammation, and dysregulated cell-death pathways. Necroptosis, a programmed form of necrotic cell death governed by the RIPK1-RIPK3-MLKL axis, has recently gained attention for its broader neuromodulatory influence beyond neuronal loss. Emerging evidence indicates that necroptotic signaling shapes the neuronal microenvironment by affecting synaptic integrity, neurotransmitter regulation, and the activity of microglia and astrocytes. Activation of necroptosis amplifies inflammatory cytokine release, disrupts neuronal communication, and contributes to the degeneration of neural circuits commonly affected in AD. In parallel, interactions between necroptotic mediators and hallmark AD features such as amyloid-β accumulation, tau phosphorylation, oxidative stress, and mitochondrial dysfunction further accelerate neurodegenerative progression. This review synthesizes current understanding of how necroptotic pathways modulate neural and glial responses in AD and highlights their contribution to disease amplification. Additionally, it discusses the therapeutic potential of targeting necroptosis using selective kinase inhibitors, genetic approaches, and advanced nanotechnology-based delivery systems aimed at restoring cellular homeostasis. Clarifying the neuromodulatory functions of necroptosis may open new avenues for therapeutic intervention and contribute to the development of more effective strategies for slowing or halting AD progression.