The mtDNA-ZBP1 axis in alzheimer's disease: Mechanisms, pathogenesis, and therapeutic implications

Alzheimer's disease (AD) is a neurodegenerative disorder, particularly prevalent in the elderly. Recent research has focused on the interplay between mitochondrial dysfunction and neuroinflammation, with the mtDNA-ZBP1 axis identified as a critical pathway linking mitochondrial function, immune response, and cell death in AD pathogenesis. Upon release into the cytoplasm, mitochondrial DNA (mtDNA) is recognized by ZBP1, triggering immune responses, inflammation, and cell death. As a central node linking mitochondrial damage, neuroinflammation, and neuronal death, ZBP1 has garnered increasing attention as both a pathogenic mechanism and a potential therapeutic target in AD. However, a comprehensive review of the mtDNA-ZBP1 axis in AD pathology and pharmacology remains lacking. This review discusses the role of the mtDNA-ZBP1 axis in AD, emphasizing how mtDNA and ZBP1 interact to activate immune responses and cell death pathways. We underscore the synergistic contribution of mitochondrial dysfunction and chronic neuroinflammation to AD progression. Additionally, we explore therapeutic strategies targeting the mtDNA-ZBP1 axis, including ZBP1 inhibitors and mtDNA stabilizers. While these strategies have shown promise in animal models, their clinical potential requires further validation. Finally, we discuss future research directions, aiming to address current challenges and advance mtDNA-ZBP1-targeted therapies toward clinical application.