Autoimmune and neuroinflammatory hypothesis in Alzheimer’s disease

Abstract

The autoimmune and neuroinflammatory hypothesis of Alzheimer's disease offers a comprehensive framework for understanding the complex interplay between the immune system and neurodegeneration. According to this model, dysregulation of autoantibodies, hyperactivation of microglia, and chronic neuroinflammation are the main mechanisms that contribute to the progression of the disease. Although autoantibodies may be a secondary response to neuronal death, their presence and dysregulated levels can amplify the inflammatory response and cause additional neuronal damage. The AD-squared model proposes that the main driving force of neurodegeneration within this hypothesis is the innate immune response, in which Aß acts as a cytokine-like immunopeptide that leads to a misdirected attack on neurons through activating microglia and releasing proinflammatory cytokines. Therefore, therapeutic intervention targeting these immune dysregulations and inflammatory processes (e.g., modulation of TREM2, inhibition of cytokines, switching of microglia phenotype to M2, restoration of retinoid balance) may represent a promising treatment strategy for AD, potentially delaying or halting the neurodegenerative cascade.