Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 119997 Moscow, Russia.
Moscow Institute of Physics and Technology, State University, 141701 Dolgoprudny, Russia.
Int J Mol Sci. 2023 Oct 3;24(19):14852. doi: 10.3390/ijms241914852.
Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, - neuromodulator Lynx1, with α7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while Aβ1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-α was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon Aβ pathology results in dysregulation of the cholinergic system and particularly of α7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration.
阿尔茨海默病（AD）是一种广泛存在的神经退行性疾病，其特征是β-淀粉样蛋白（Aβ1-42）的寡聚毒性形式的积累和不同脑区胆碱能系统的功能障碍。然而，AD 发病机制的确切机制以及烟碱型乙酰胆碱受体（nAChRs）在疾病进展中的作用仍不清楚。在这里，我们发现在 2xTg-AD 小鼠（早期 AD 模型）的小脑与非转基因小鼠相比，许多针对 nAChRs 的 Ly6/uPAR 蛋白的表达在 mRNA 和蛋白质水平上均降低。我们表明，其中一种蛋白，神经调节剂 Lynx1，与 2xTg-AD 小鼠小脑星形胶质细胞附近的α7-nAChR 的共定位减少，而存在的 Aβ1-42 与该受体的共定位增加。此外，调节基因转录的抗炎转录因子 KLF4 的表达在 2xTg-AD 小鼠的小脑减少，而炎症细胞因子 TNF-α的表达增加。基于这些数据以及在 2xTg-AD 小鼠小脑观察到的星形胶质细胞变性，我们提出了在 Aβ 病理条件下 Ly6/uPAR 蛋白表达导致小脑胆碱能系统失调，特别是 α7-nAChR 功能失调的机制。这导致神经炎症增强和小脑星形胶质细胞变性。
