Mechanisms of MDK Upregulation in Early Alzheimer's Disease and Its Impact on Aβ Clearance Through Microglial Regulation

Recent studies have demonstrated upregulation of midkine (MDK) in the brains of 5xFAD mice, and MDK knockout exacerbates amyloid plaque formation and microglial activation. However, the molecular mechanism of MDK upregulation in Alzheimer's disease (AD) pathology and its effect on microglial-mediated Aβ clearance remain unclear. The study hypothesizes that the co-localization of MDK with Aβ and the MDK-Aβ interaction may alter microglial recognition and processing of plaques, which contributes to AD pathology. In this study, 5xFAD transgenic mice will be utilized to determine the distribution of MDK, analyze the MDK expression and subcellular localization in microglia, characterize the binding affinity of MDK Aβ and evaluate the effects of MDK Aβ complexes on microglia. Consequently, this study is expected to elucidate the molecular mechanism of MDK accumulation in the AD brain and its regulatory role in microglial phagocytosis, providing an experimental basis for the development of MDK‑targeted therapeutic strategies.