[Research progress on the correlation mechanism between innate immune imbalance and Alzheimer's disease based on Drosophila model].

Abstract

Innate immune dysregulation is a common pathological basis for the development and progression of both infectious diseases and various chronic diseases. Drosophila melanogaster, owing to its highly conserved immune system, well-established genetic manipulation tools, and intact in vivo physiological environment, has become an important model for studying human immune-related diseases. This article systematically reviews the latest research progress on the Drosophila model regarding the "infection-innate immune dysregulation-Alzheimer's disease (AD)" axis. Studies using Drosophila models have shown that Gram-positive bacteria and fungi activate the Toll pathway, while Gram-negative bacteria activate the immune deficiency (Imd) pathway, leading to innate immune dysregulation; all of the above pathogen infections are associated with the pathological progression of AD. Peripheral immune dysregulation can mediate cross-organ inflammatory transmission through the gut-brain axis and the oral-gut-brain axis, thereby contributing to the exacerbation of AD pathological damage. The Drosophila tumor necrosis factor α (TNF-α) homolog Eiger, via activation of the tumor necrosis factor-c-Jun N-terminal kinase (TNF-JNK) pathway, mediates peripheral-immune-driven remote central neuroinflammation. These findings suggest that precise regulation of the innate immune system is critical for maintaining organismal homeostasis, and its dysregulation serves as a link between infectious diseases and AD. The Drosophila model provides a unique perspective for dissecting the pathological progression of "infection-innate immune dysregulation-AD," laying a theoretical foundation for AD intervention strategies targeting immune pathways, the gut-brain axis, and the oral-gut-brain axis, and also offering a reference for translational research on innate immunity-related diseases. It should be noted that the above conclusions are mainly based on mechanistic studies in the Drosophila model, and their extrapolation to human AD still requires further validation.