Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Sede Building, 3rd Floor, Barrio de Sarriena s/n, 48940 Leioa, Spain.
Department of Neurosciences, Faculty of Medicine and Nursery UPV/EHU and CIBERNED, Barrio de Sarriena s/n, 48940 Leioa, Spain.
Int J Mol Sci. 2022 May 20;23(10):5747. doi: 10.3390/ijms23105747.
Glial cells participate actively in the early cognitive decline in Alzheimer's disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD. A recent study from our laboratory reports that astrocyte reactivity is caused by a direct interaction between amyloid beta (Aβ) oligomers and integrin β1. Here, we have generated four recombinant peptides including the extracellular domain of integrin β1, and evaluated their capacity both to bind in vitro to Aβ oligomers and to prevent in vivo Aβ oligomer-induced gliosis and endoplasmic reticulum stress. We have identified the minimal region of integrin β1 that binds to Aβ oligomers. This region is called signal peptide and corresponds to the first 20 amino acids of the integrin β1 N-terminal domain. This recombinant integrin β1 signal peptide prevented Aβ oligomer-induced ROS generation in primary astrocyte cultures. Furthermore, we carried out intrahippocampal injection in adult mice of recombinant integrin β1 signal peptide combined with or without Aβ oligomers and we evaluated by immunohistochemistry both astrogliosis and microgliosis as well as endoplasmic reticulum stress. The results show that recombinant integrin β1 signal peptide precluded both astrogliosis and microgliosis and endoplasmic reticulum stress mediated by Aβ oligomers in vivo. We have developed a molecular tool that blocks the activation of the molecular cascade that mediates gliosis via Aβ oligomer/integrin β1 signaling.
神经胶质细胞积极参与阿尔茨海默病（AD）病理的早期认知衰退。事实上，最近的研究在动物模型和患有该病理的患者的大脑中发现了星形胶质细胞和小胶质细胞的分子和功能异常。在这方面，与淀粉样斑块密切相关的反应性神经胶质增生已成为 AD 的病理标志。我们实验室最近的一项研究报告称，星形胶质细胞反应性是由淀粉样β（Aβ）寡聚体和整合素β1之间的直接相互作用引起的。在这里，我们生成了四个包含整合素β1胞外结构域的重组肽，并评估了它们在体外结合 Aβ寡聚体的能力以及在体内预防 Aβ寡聚体诱导的神经胶质增生和内质网应激的能力。我们确定了整合素β1与 Aβ寡聚体结合的最小区域。该区域称为信号肽，对应于整合素β1 N 端结构域的前 20 个氨基酸。这种重组整合素β1信号肽可防止原代星形胶质细胞培养物中 Aβ寡聚体诱导的 ROS 生成。此外，我们在成年小鼠海马内注射重组整合素β1信号肽与 Aβ寡聚体结合或不结合，并通过免疫组织化学评估星形胶质细胞和小胶质细胞增生以及内质网应激。结果表明，重组整合素β1信号肽可防止 Aβ寡聚体在体内介导的星形胶质细胞和小胶质细胞增生以及内质网应激。我们开发了一种分子工具，可阻断通过 Aβ寡聚体/整合素β1信号介导的神经胶质细胞激活的分子级联。
