Alzheimer's disease (AD) represents a primary contributor to cognitive deterioration in the elderly population. Mitochondrial dysfunction, which is closely associated with microtubule instability, contributes to AD progression. TUBB2A, a key microtubule protein, is essential for mitochondrial transport and neuronal function. This study investigates how DNA methylation of FGF13 affects mitochondrial function and its role in AD via the FGF13/TUBB2A axis. AD mouse models were established by injecting Aβ25-35 into the hippocampus, and dual-fluorescence staining was employed to quantify the expression levels of FGF13 and TUBB2A in different neural cell types in brain tissue. Western blotting assessed microtubule stability and mitochondrial function in the hippocampus. Nissl and TUNEL staining were used to detect neuronal survival and apoptosis, and transmission electron microscopy was used to observe the ultrastructure of mitochondria. Flow cytometry was employed to determine mitochondrial membrane potential in hippocampal tissue, and Methylation-Specific PCR was used to detect the methylation levels of FGF13. Co-immunoprecipitation experiments verified the interaction between FGF13 and TUBB2A. Mitochondrial dysfunction exists in the hippocampal tissue of AD mice. Overexpression of FGF13 alleviated mitochondrial ROS, enhanced microtubule stability, increased mitochondrial membrane potential, and reduced neuronal apoptosis, thereby improving symptoms. FGF13 was found to be methylated, and its methylation affected its direct binding with TUBB2A. Overexpression of FGF13's protective effects on neurons could be reversed by knocking down TUBB2A. The expression of FGF13 is reduced in AD mouse neurons, which is associated with its high methylation state. Overexpression of FGF13 improves microtubule stability and mitochondrial function in hippocampal neurons through interaction with TUBB2A, suggesting a potential therapeutic relevance in AD.
Ren et al. (Tue,) studied this question.