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

• Published in: CNS neuroscience & therapeutics 2024-10, Vol.30 (10), p.e70064-n/a
• Main Authors: Ma, Xiang, Sun, Yusheng, Li, Changchun, Wang, Man, Zang, Qijiao, Zhang, Xuxia, Wang, Feng, Niu, Yulan, Hua, Jiai
• Format: Article
• Language: English
• Subjects: 5xFAD transgenic model; Acetyltransferase; Acetyltransferases - genetics; Acetyltransferases - metabolism; Algorithms; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Cognitive ability; Copper; Copper - metabolism; Copper - toxicity; Datasets; Death; Dehydrogenases; Disease; Exosomes; Exosomes - metabolism; exosome‐mediated signaling; Extracellular vesicles; Gene expression; gene expression profiling in AD; Hippocampus; Homeostasis; Humans; Humidity; Machine learning; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; neurodegeneration mechanisms; Neurodegenerative diseases; neuronal copper toxicity; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurotoxicity; Original; Pathogenesis; Pathology; Proteins; Pyruvate kinase; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Pyruvic acid; Sulfur; Support vector machines; therapeutic target discovery; Therapeutic targets; Toxicity; Transgenic mice
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/cns.70064

ABSTRACT 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. Schematic representation of the molecular mechanism by which extracellular vesicles derived from microglia deliver PKM2 to regulate DLAT expression, influencing neuronal copper‐induced death and AD progression.