恢复活力的免疫细胞可以更好地清除大脑中的有毒废物gydF4y2Ba
![PBMs are distinct from microglia and sample CSF and ISF. a , CD206+ PBMs (cyan) are easily distinguishable from IBA1+ microglia (yellow) and are located at the vicinity of i.v. lectin+ large blood vessels (red). Scale bar, 100 μm. b , PBMs are located outside of the brain vasculature, in the perivascular space. c , Quantification of whole brain sections showing spatial distribution of PBMs through both perivascular space (PVS) and leptomeninges (LM). Scale bar, 20 μm. n = 5 mice. d , Gating strategy for PBM detection. PBMs were defined as DAPI − CD45 + TCRb − CD19 − CD11b + CD64 hi F4/80 hi CD206 + cells. PBMs can be divided in subtypes using MHCII and CD38. e , WT mice received an i.c.m. injection of Alexa-647 conjugated ovalbumin (OVA; 45 kDa; 1 mg/ml; 5 μl). One hour after OVA injection, mice received an i.v. injection of Alexa-594 conjugated lectin (30 μl) and were perfused five minutes later. Maximum projection image obtained by light sheet microscopy from a cleared mouse brain showing brain OVA (magenta) distribution at the vicinity of i.v.-injected lectin+ blood vessels (cyan). Scale bar, 1mm. f , WT mice received an i.c.m. injection of Alexa-647 conjugated ovalbumin (OVA; 45 kDa; 1 mg/ml; 5 μl). Mice were perfused one hour after OVA injection. Representative stereomicroscopy images showing whole brain OVA distribution from the distal part of the middle cerebral artery (MCA), and quantification of both perivascular and cellular OVA distribution. Scale bars, 1mm and 200 μm (inset). n = 6 mice. g , Experimental schematic: WT mice received an i.c.m. injection of FITC Dextran (FITCDex; 4 kDa; 10 mg/ml; 5 μl) and brain were harvested one hour later. Brain coronal sections were stained for anti-CD206 (cyan) and DAPI. Scale bars, 2 mm and 50 μm (insets). h , Experimental schematic: WT mice received an intrastriatal (i.s.) injection of a cocktail containing 0.5 μl of FITC-Dex (10mg/ml; green) and 0.5 μl of OVA (1 mg/ml; magenta) and brains were harvested one hour later. Brains were then stained for anti-CD206 (cyan). Scale bars, 2 mm and 50 μm (insets). i , Mice received an i.s. injection of A488-OVA (green) and an i.c.m. injection of A647-OVA (magenta) one hour later. Mice were perfused one hour later (two hours after the i.s. injection). Some cells sampled both i.s. and i.c.m. OVAs. Scale bars, 2 mm and 100 μm (inset). All data are presented as mean values +/− SEM. Credit: Nature (2022). DOI: 10.1038/s41586-022-05397-3 恢复活力的免疫细胞可以更好地清除大脑中的有毒废物gydF4y2Ba](https://scx1.b-cdn.net/csz/news/800a/2022/rejuvenated-immune-cel.jpg)
阿尔茨海默氏症、帕金森氏症和许多其他神经退行性疾病的特征是大脑中破坏性的蛋白质簇。科学家们花费了巨大的努力,通过清除这些有毒物质来寻找治疗这种疾病的方法,但收效甚微。gydF4y2Ba
现在,圣路易斯华盛顿大学医学院的研究人员发现了一种创新的方法来提高大脑废物的清除,从而可能治疗甚至预防神经退行性疾病。他们发现,大脑周围的免疫细胞会影响废物被清除出大脑的效率,而在老年小鼠以及患有阿尔茨海默病的人和小鼠身上,这种免疫细胞会受损。gydF4y2Ba
此外,他们发现用一种免疫刺激化合物治疗老年小鼠可以使免疫细胞恢复活力,并改善大脑中的废物清除。gydF4y2Ba
该研究结果发表在gydF4y2Ba自然gydF4y2Ba,提出了一种新的方法来阻止衰老对大脑的一些影响。gydF4y2Ba
资深作者Jonathan Kipnis博士、Alan a .和Edith L. Wolff病理学与免疫学特聘教授和BJC研究员说:“从神经元如何死亡的角度研究阿尔茨海默氏症已有多年,但还有其他细胞,如大脑外围的免疫细胞,也可能在阿尔茨海默氏症中发挥作用。”gydF4y2Ba
“我们似乎不太可能复活死亡或垂死的神经元,但位于大脑边缘的免疫细胞是治疗与年龄相关的脑部疾病的可行靶点。它们更容易获得,而且可以被下药或替换。在这项研究中,我们用一种可以激活衰老免疫细胞的分子治疗老年小鼠,并起到了改善作用gydF4y2Ba流体流动gydF4y2Ba并清除大脑中的废物。这有望成为治疗神经退行性疾病的一种方法。”gydF4y2Ba
Kipnis是神经免疫学领域的专家,该领域研究免疫系统如何在健康和疾病中影响大脑。2015年,他发现了一个血管网络,可以将液体、免疫细胞和小分子从大脑排入大脑gydF4y2Ba淋巴结gydF4y2Ba这是许多免疫系统细胞居住的地方。去年,他和同事们证明,当与一种旨在改善大脑液体和碎片排出的治疗方法搭配使用时,一些处于研究阶段的阿尔茨海默氏症疗法在小鼠身上更有效。gydF4y2Ba
在这项研究中,Kipnis和Antoine Drieu博士(博士后研究员,论文的主要作者)着手了解生活在大脑脉管系统和轻脑膜(紧邻大脑和脊髓的组织)中的免疫细胞所起的作用。他们称这些细胞为实质边界巨噬细胞,因为它们位于两者之间的界面gydF4y2Ba脑脊髓液gydF4y2Ba还有脑组织。gydF4y2Ba
通过对小鼠的研究,Kipnis、Drieu和同事们发现,这种巨噬细胞调节着动脉的运动,进而控制着流经大脑的液体的清洁流动。当这些巨噬细胞耗尽或受损时,碎片就会在大脑中堆积起来。gydF4y2Ba
“许多人的脑脊液流动受损gydF4y2Ba神经退行性疾病gydF4y2Ba比如阿尔茨海默氏症、中风、帕金森症和多发性硬化症,”德里欧说。“如果我们可以通过促进这些巨噬细胞来恢复大脑中的液体流动,也许我们可以减缓这些疾病的进展。这是个梦,但谁知道呢?可能会有用。”gydF4y2Ba
进一步的调查显示,阿尔茨海默病患者和阿尔茨海默病样小鼠的实质边界巨噬细胞发生了改变gydF4y2Ba免疫细胞gydF4y2Ba消耗和处理废物的能力较差,不能有效地调节流体流量。gydF4y2Ba
从大约50岁开始,作为正常衰老的一部分,人们开始经历脑液流量的下降。同样的事情也发生在年老的老鼠身上。Kipnis, Drieu和他的同事发现,在老年小鼠中,对废物清除和液体流动最重要的边界巨噬细胞很少。当他们治疗时gydF4y2Ba老老鼠gydF4y2Ba有了一种促进巨噬细胞活性的蛋白质,边缘巨噬细胞开始表现得更像年轻小鼠的巨噬细胞。此外,这种治疗改善了小鼠大脑的液体流动和废物清除。gydF4y2Ba
“总的来说,我们的研究结果表明,实质边界巨噬细胞可能在药理学上被靶向,以缓解与衰老和阿尔茨海默病相关的大脑清除缺陷,”Kipnis说,他也是神经学、神经科学和神经外科的教授。“我正在和同事们讨论如何在老化的大脑中替换或恢复这些细胞,并作为阿尔茨海默病的治疗方法。我希望有一天我们能够减缓或延缓与年龄相关的发展gydF4y2Ba大脑gydF4y2Ba用这种方法来治疗疾病。”gydF4y2Ba