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: 10012629
• 负责人: Arya Biragyn
• 金额: $ 54.1万
• 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/10012629
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Antibodies; Anxiety; B-Lymphocytes; Blood Circulation; Brain; Cells; Disease; Exhibits; Goals; Human; Immune; Inflammatory; Memory impairment; Microglia; Mus; Neurons; Onset of illness; Pathogenicity; Pathology; Play; Production; Role; Symptoms; Testing; Therapeutic; Time; Transgenic Organisms; Vaccines; abeta deposition; aged; improved; mouse model; neurotoxic; sex; therapeutic target

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). Therefore, to understand their role in AD, we evaluated B cells in transgenic AD mice (3xTgAD mice). To our surprise, we found that B cells expressing inflammatory factors were markedly enriched in the circulation of mice with AD as compared with healthy control mice. Because we previously demonstrated that similar B cells also accumulate and promote aging-associated pathologies in aged mice and humans, we hypothesized whether these B cells are to exacerbate AD. To test this idea, 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. Our results revealed that AD symptoms were markedly ameliorated in both 2xTgAD and 3xTgAD mice if B cells were lost. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. Despite high levels of APP production in neurons, 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. Thus, B cells appeared to play pathogenic role in AD, implying that they can be therapeutic targets for the delay of AD onset. We tested this idea in 3 different mouse models of AD, such as 2xTgAD, 3xTgAD, and 5xFAD mice by treating them with B-cell depleting antibody at the onset of the diseases. The treatment indeed significantly delayed AD symptoms in all three types of mice. Overall, our study for the first time demonstrate that B cells play pathogenic role in AD. Importantly, we also show that the AD onset can be delayed by therapeutic depletion of B cells.

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）。因此，为了了解它们在 AD 中的作用，我们评估了转基因 AD 小鼠（3xTgAD 小鼠）中的 B 细胞。令我们惊讶的是，我们发现与健康对照小鼠相比，AD 小鼠循环中表达炎症因子的 B 细胞显着富集。因为我们之前证明类似的 B 细胞也会在老年小鼠和人类中积累并促进与衰老相关的病理，因此我们假设这些 B 细胞是否会加剧 AD。 为了测试这个想法，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。我们的结果显示，如果 B 细胞丢失，2xTgAD 和 3xTgAD 小鼠的 AD 症状均显着改善。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。尽管神经元中 APP 产生量较高，但 2xTgAD/BKO 和 3xTgAD/BKO 小鼠的脑下托中含有的 Ab 斑块明显少于其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。因此，B细胞似乎在AD中发挥致病作用，这意味着它们可以成为延迟AD发病的治疗靶点。我们在 3 种不同的 AD 小鼠模型（例如 2xTgAD、3xTgAD 和 5xFAD 小鼠）中测试了这一想法，方法是在疾病发作时用 B 细胞消耗抗体对其进行治疗。 这种治疗确实显着延迟了所有三种小鼠的 AD 症状。总体而言，我们的研究首次证明 B 细胞在 AD 中发挥致病作用。重要的是，我们还表明，B 细胞的治疗性耗竭可以延迟 AD 的发作。