Alzheimer's disease (AD) is a neurodegenerative disorder with unclear etiology. This study employs single-cell RNA sequencing (scRNA-seq), high-throughput transcriptome sequencing, 16s rRNA sequencing, and animal experiments to investigate the role of the contactin-associated protein like-4 (Cntnap4) gene in AD and its interaction with intestinal flora. We found that Cntnap4 deficiency in AD mice led to increased Tau protein phosphorylation, amyloid-beta plaque accumulation, and neuronal loss. Astrocytes in Cntnap4 −/− mice showed impaired amyloid-beta processing. 16 s rRNA sequencing revealed distinct intestinal flora compositions between Cntnap4 −/− and control mice, indicating a potential link between gut microbiota and AD progression. Notably, GABA supplementation improved cognitive impairment, restored synaptic currents, reduced amyloid-beta plaques, and increased neuronal counts. This study highlights Cntnap4's critical role in AD and suggests gut-brain axis involvement, offering novel insights for potential therapeutic strategies.
Wentao Hu,Menghan Wang,Guifang Sun,Limin Zhang,Hong Lu
Parkinson's disease (PD) is a gradually debilitating neurodegenerative syndrome. Here, we analyzed GSE7621 chip data obtained from the Gene Expression Omnibus (GEO) database to explore the pathogenesis of PD. Early B Cell Factor 3 (EBF3), a member of the highly evolutionarily conserved EBF-transcription factor family, is involved in neuronal development. EBF3 expression is low in the substantia nigra of patients with PD. However, whether EBF3 is implicated in dopaminergic neuron death during PD has not yet been investigated. Therefore, we aimed to reveal the potential anti-apoptotic effect and molecular mechanism of EBF3 in PD. We established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model in vivo and a 1-methyl-4-phenylpyridine (MPP + )-induced SH-SY5Y cell model in vitro . EBF3 was downregulated in the substantia nigra of PD mice and SH-SY5Y cells treated with MPP + , and the m6A methylation modification level was low. Fat mass and obesity-associated protein (FTO) siRNA upregulated m6A methylation modification of EBF3 and extended the EBF3 mRNA half-life. Functionally, as demonstrated by the results of the open-field test, pole test and gait analysis, EBF3 overexpression ameliorated MPTP-induced behavioral disorder. Further, EBF3 overexpression suppressed neuronal apoptosis in vivo , as evidenced by decreased TUNEL + cells, and the increased activation of caspase-3 and caspase-9. Similar results were obtained in vitro , as reflected by increased cell viability, decreased LDH activity and restored mitochondrial function, collectively protecting SH-SY5Y cells from MPP + -induced apoptosis. Mechanistically, the results of luciferase reporter, ch-IP and DNA pull-down assays confirmed that, as a transcription factor, EBF3 bound to the promoter of CNTNAP4 (a protein associated with neuronal differentiation) and directly regulated CNTNAP4 transcription. Strikingly, CNTNAP4 knockdown markedly abolished the effect of EBF3 on cell apoptosis, thus aggravating PD. In conclusion, the low level of m6A methylation modification may contribute to the low expression of EBF3 during PD. Additionally, EBF3 attenuates PD by activating CNTNAP4 transcription, suggesting that EBF3 may be a novel therapeutic target in PD.
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