Foley Kate E, Weekman Erica M, Krick Katelynn E, Johnson Sherika N, Sudduth Tiffany L, Wilcock Donna M
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Neurology, School of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202.
J Neurosci. 2025 Jan 29;45(5):e1456242024. doi: 10.1523/JNEUROSCI.1456-24.2024.
Anti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain, there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study, we sought to identify the acute effects of anti-Aβ antibodies on immune responses. To determine cellular changes due to anti-Aβ antibody exposure, we intracranially injected 14 mo APP male and female mice with anti-Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24 h or 3 d, we harvested the cortex and performed a glial cell-enriched preparation for single-cell sequencing. Cell types, proportions, and cell-to-cell signaling were evaluated between the two injection conditions and two acute timepoints. We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti-Aβ antibody-injected cortices revealed more ligand-receptor (L-R) communications between cell types, as well as stronger communications at only 24 h. At 3 d, while there were more L-R communications for the anti-Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. We also found evidence of an initial and strong communication emphasis in microglia-to-nonparenchymal immune cells at 24 h, specifically in the TGFβ signaling pathway. We identify several pathways that are specific to anti-Aβ antibody exposure at acute timepoints. These data lay the groundwork for understanding the brain's unique response to anti-Aβ antibodies.
用于治疗阿尔茨海默病的抗淀粉样前体蛋白（Aβ）免疫疗法正在兴起。虽然抗Aβ抗体为靶向大脑中的Aβ斑块带来了希望，但对于大脑中这些抗体的细胞反应仍缺乏了解。在本研究中，我们试图确定抗Aβ抗体对免疫反应的急性影响。为了确定抗Aβ抗体暴露引起的细胞变化，我们向14月龄的APP雄性和雌性小鼠颅内注射抗Aβ IgG1（6E10）或对照IgG1至皮质。24小时或3天后，我们收获皮质并进行富含胶质细胞的制备用于单细胞测序。在两种注射条件和两个急性时间点之间评估细胞类型、比例和细胞间信号传导。我们鉴定出23个独特的细胞簇，包括小胶质细胞、星形胶质细胞、内皮细胞、神经元、少突胶质细胞/少突胶质前体细胞、免疫细胞和未知细胞。注射抗Aβ抗体的皮质显示细胞类型之间有更多的配体-受体（L-R）通讯，并且仅在24小时时通讯更强。在3天时，虽然抗Aβ抗体条件下有更多的L-R通讯，但这些连接的强度在对照IgG条件下更强。我们还发现证据表明在24小时时小胶质细胞与非实质免疫细胞之间存在初始且强烈的通讯重点，特别是在转化生长因子β（TGFβ）信号通路中。我们确定了几个在急性时间点对抗Aβ抗体暴露具有特异性的信号通路。这些数据为理解大脑对抗Aβ抗体的独特反应奠定了基础。
