Pyroptosis in Alzheimer's Disease: Mechanisms and Therapeutic Potential.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Recent research has revealed that pyroptosis, an inflammatory programmed cell death (PCD), plays a crucial role in AD pathology. The pyroptosis signaling cascade triggered by β-amyloid (Aβ) and hyperphosphorylated tau protein leads to the release of proinflammatory cytokines, forming a "neuroinflammation-neurodegeneration" vicious cycle. Therapeutic strategies targeting the pyroptosis signaling pathway show promise, with evidence suggesting that inhibition of inflammasomes, caspase-1, or gasdermin D (GSDMD) can alleviate AD-related pathological features. However, the specificity of the existing inhibitors is insufficient, and research on non-classical pyroptosis pathway remains in its early stages. More mechanisms and therapeutic strategies targeting pyroptosis-related pathway need to be explored to enhance the therapeutic efficacy. Targeting the pyroptosis pathway provides a novel direction for AD treatment. Exploring and summarizing its mechanisms along with the clinical translational applications of targeted inhibitors will offer fresh perspectives for moving beyond traditional "symptom control" therapies and achieving "pathology-modifying" interventions, holding significant scientific and clinical importance.