The role of immune cells in Alzheimer's disease

免疫细胞在阿尔茨海默病中的作用

• 批准号: 10250898
• 负责人: Arya Biragyn
• 金额: $ 52.89万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10250898
• 关键词: APP-PS1; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Antibodies; Anxiety; B-Lymphocytes; Back; Blood Circulation; Brain; COVID-19; Cells; Complement; Disease; Down Syndrome; Exhibits; Goals; Immune; Inflammatory; MS4A1 gene; Memory impairment; Microglia; Mus; Onset of illness; Paper; Pathogenicity; Play; Publications; Published Comment; Quarantine; Role; Symptoms; Testing; Therapeutic; Time; Transgenes; Vaccines; abeta deposition; experimental study; improved; mouse model; neurotoxic; sex

The role of B cells in Alzheimer's disease (AD) remains poorly understood even though we and others showed their benefit as producers of antibody that help to eliminate neurotoxic beta-amyloid depositions (Ab plaques) (Olkhanud et al, Vaccine, 2011). About 6 years ago, we have hypothesized that B cells could also be promoting AD because they upregulate expression of inflammatory factors together with the onset of AD in 3xTgAD mice. We tested this possibility in 3 different mouse models of AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, utilizing complementing experimental strategies. First, we generated B-cell deficient (BKO) mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice by crossing BKO mice with 2xTgAD and 3xTgAD mice, respectively. The loss of B cells in these mice almost completely reversed the AD symptoms despite expression of AD-promoting transgenes. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. Both 2xTgAD/BKO and 3xTgAD/BKO mice contained significantly fewer Ab-plaques in the brain subiculum than their age- and sex-matched littermates. The over activated microglia, another hallmark of AD pathology, in both mice without B cells was also markedly reduced. To confirm this finding, we also transiently depleted B cells from the circulation of mice with AD, such as 3xTgAD, APP/PS1 and 5xFAD mice, by injecting CD20-targeting antibody. The B-cell depletion indeed significantly delayed AD symptoms in all three types of mice. Overall, for the first time we demonstrate that B cells play pathogenic role in AD and, importantly, their transient depletion from the circulation can delay AD onset. The paper, which we recently submitted for publication, came back for revision. Due to the COVID-19 quarantine, we had to terminate experiments and cull essential AD mice, precluding a proper addressing the editor and reviewers comments. We therefore expect to finalize this paper by middle of 2021. Despite this, we have played the key roles in successful completion of 2 papers from our collaborators on Ad and AD-like symptoms in Down syndrome.

尽管我们和其他人展示了 B 细胞作为抗体产生者的益处，有助于消除神经毒性 β-淀粉样蛋白沉积（Ab 斑块），但 B 细胞在阿尔茨海默病 (AD) 中的作用仍然知之甚少（Olkhanud 等人，疫苗，2011）。大约 6 年前，我们假设 B 细胞也可能促进 AD，因为它们在 3xTgAD 小鼠中上调炎症因子的表达以及 AD 的发作。我们利用补充实验策略在 3 种不同的 AD 小鼠模型（例如 3xTgAD、APP/PS1 和 5xFAD 小鼠）中测试了这种可能性。首先，我们通过将 BKO 小鼠分别与 2xTgAD 和 3xTgAD 小鼠杂交，产生了在年轻和年老时发生 AD 的 B 细胞缺陷 (BKO) 小鼠、2xTgAD 和 3xTgAD 小鼠。尽管表达了促进 AD 的转基因，但这些小鼠 B 细胞的丧失几乎完全逆转了 AD 症状。与年龄/性别匹配的 B 细胞充足的同窝小鼠相比，2xTgAD/BKO 和 3xTgAD/BKO 小鼠表现出焦虑减轻和记忆缺陷改善。 2xTgAD/BKO 和 3xTgAD/BKO 小鼠的脑下托中含有的 Ab 斑块明显少于年龄和性别匹配的同窝小鼠。在两只没有 B 细胞的小鼠中，过度激活的小胶质细胞（AD 病理学的另一个标志）也显着减少。为了证实这一发现，我们还通过注射 CD20 靶向抗体，暂时消除了 AD 小鼠（例如 3xTgAD、APP/PS1 和 5xFAD 小鼠）循环中的 B 细胞。 B 细胞耗竭确实显着延迟了所有三种小鼠的 AD 症状。总体而言，我们首次证明 B 细胞在 AD 中发挥致病作用，重要的是，B 细胞在循环中的短暂消耗可以延迟 AD 的发病。我们最近提交出版的这篇论文被返回进行修改。由于 COVID-19 隔离，我们不得不终止实验并剔除必要的 AD 小鼠，从而无法正确处理编辑和审稿人的评论。因此，我们预计在 2021 年中期完成这篇论文。尽管如此，我们在合作者成功完成两篇关于唐氏综合症 AD 和 AD 样症状的论文中发挥了关键作用。