Novel Insights Into DLAT's Role in Alzheimer's Disease-Related Copper Toxicity Through Microglial Exosome Dynamics.

BACKGROUND

Alzheimer's disease (AD) is a complex neurodegenerative disorder, with recent research emphasizing the roles of microglia and their secreted extracellular vesicles in AD pathology. However, the involvement of specific molecular pathways contributing to neuronal death in the context of copper toxicity remains largely unexplored.

OBJECTIVE

This study investigates the interaction between pyruvate kinase M2 (PKM2) and dihydrolipoamide S-acetyltransferase (DLAT), particularly focusing on copper-induced neuronal death in Alzheimer's disease.

METHODS

Gene expression datasets were analyzed to identify key factors involved in AD-related copper toxicity. The role of DLAT was validated using 5xFAD transgenic mice, while in vitro experiments were conducted to assess the impact of microglial exosomes on neuronal PKM2 transfer and DLAT expression. The effects of inhibiting the PKM2 transfer via microglial exosomes on DLAT expression and copper-induced neuronal death were also evaluated.

RESULTS

DLAT was identified as a critical factor in the pathology of AD, particularly in copper toxicity. In 5xFAD mice, increased DLAT expression was linked to hippocampal damage and cognitive decline. In vitro, microglial exosomes were shown to facilitate the transfer of PKM2 to neurons, leading to upregulation of DLAT expression and increased copper-induced neuronal death. Inhibition of PKM2 transfer via exosomes resulted in a significant reduction in DLAT expression, mitigating neuronal death and slowing AD progression.

CONCLUSION

This study uncovers a novel pathway involving microglial exosomes and the PKM2-DLAT interaction in copper-induced neuronal death, providing potential therapeutic targets for Alzheimer's disease. Blocking PKM2 transfer could offer new strategies for reducing neuronal damage and slowing disease progression in AD.