[Role of the JAK2/STAT3 pathway in aluminium-induced synaptic function impairment]

Objective: To investigate the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in aluminum-induced synaptic function impairment. Methods: In March 2024, twenty-four SPF-grade C57BL/6J mice were randomly divided into four groups using the random number table method: the control group (normal saline) and the low, medium, and high-dose aluminium exposure groups [20, 40, and 80 μmol/kg aluminum maltol]. The exposure period lasted for 3 months. After treatment, the Morris water maze test was performed to evaluate the effects of aluminum maltol on learning and memory ability of mice. The expression levels of JAK2/STAT3 pathway proteins, postsynaptic density protein 95 (PSD95), and synapsinⅠ (SYNⅠ) were detected by Western blotting. HT22 mouse hippocampal neuronal cells were used for in vitro experiments, which were divided into the aluminum exposure group [control group (blank group), low, medium, and high-dose groups (60, 120, and 240 μmol/L aluminum maltol) ] and the intervention group[control group (blank group), Colivelin (JAK2/STAT3 pathway activator) group, aluminum maltol group (120 μmol/L), and Colivelin+aluminum maltol group]. Cell viability was tested using CCK-8, morphological changes were observed under an inverted microscope, and the expression levels of JAK2 and STAT3 genes were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression levels of JAK2/STAT3 pathway proteins, PSD95, and SYN Ⅰ were detected by Western blotting, and the fluorescence intensity of PSD95 and SYN Ⅰ proteins was detected by immunofluorescence staining. One-way analysis of variance was used for inter-group difference analysis, and LSD-t test was used for pairwise comparison if the variances were homogeneous, otherwise, Dunnett's T3 test was adopted. Results: The Morris water maze test showed that on the 4th and 5th days of the place navigation trial, the escape latency of mice in the medium and high-dose groups were significantly prolonged compared with the control group (P<0.05). In the spatial probe trial, the number of platform crossings and the time spent in the target quadrant were significantly reduced in the medium and high-dose groups compared with the control group (P<0.05). Western blotting analysis showed that the protein expression levels of JAK2, phosphorylated JAK2, STAT3, phosphorylated STAT3, PSD95, and SYN Ⅰ in the hippocampus were significantly decreased in the medium and high-dose groups compared with the control group (P<0.05). Compared with the control group, the cell viability of HT22 cells in the medium and high-dose groups were decreased (P<0.05) ; compared with the control group and the low-dose group, the number and length of the synaptic connections in the medium and high-dose groups were reduced (P<0.05) ; compared with the control group and the low-dose group, the mRNA expression levels of JAK2 and STAT3 and the protein expression levels of JAK2, phosphorylated JAK2, and SYNⅠ in the medium and high-dose groups were all decreased (P<0.05) ; the differences in the protein expression levels of STAT3, phosphorylated STAT3, and PSD95 in each dose group were statistically significant (P<0.05) ; compared with the control group, the fluorescence intensities of PSD95 and SYN Ⅰ proteins in the medium and high-dose groups were decreased (P<0.05). In addition, compared with the aluminum maltol group, the number of synaptic connections between HT22 cells in the Colivelin+aluminum maltol group increased and the length of the connections became longer (P<0.05) ; compared with the aluminum maltol group, the expression of JAK2 mRNA in the Colivelin+aluminum maltol group was increased (P<0.05), and the expressions of JAK2, phosphorylated JAK2, phosphorylated STAT3, PSD95 and SYNⅠ proteins were all increased (P<0.05), and the fluorescence intensities of PSD95 and SYN Ⅰ proteins were also increased (P<0.05) . Conclusion: Aluminium maltol can lead to synaptic function impairment, and the JAK2/STAT3 signaling pathway may be involved in the related regulation.