ABCA7

*仅供医学专业人士阅读参考阿尔茨海默病（AD）可以“人传人”？莫慌，严格意义上来说，此传染非彼传染，AD不是流感那样的传染病。不过，科学家们确实提出了AD的“病原体”——β淀粉样蛋白（Aβ）。今日，《自然·医学》杂志发表了来自伦敦大学学院John Collinge团队的新成果。这位学者算得上老朋友，此前他们曾发现，尸源性人生长激素（c-hGH）中的Aβ能够诱导小鼠出现Aβ沉积，为AD的传染假说提供了印证。此次，他们分析了8例童年曾接受c-hGH治疗者的病例，发现其中部分患者出现了早发性AD的症状和脑内的Aβ斑块沉积，同时，这些人并未携带早发性AD的风险基因。这无疑是医源性Aβ可促进AD进展的有力证据。论文题图蛋白也可以是病原体，这个认知想必大家并不陌生，朊病毒和疯牛病的故事已经告诉我们很多。与之类比，AD等以异常蛋白积累为核心病理的多种神经退行性疾病也存在类似的传染假说。这件事还要从上个世纪说起。早在1950年代，就有人为身高所困寻求治疗。但是受限于当时的技术水平，治疗所需的生长激素只能从过世者的脑垂体中提取，也就是前文我们所提到的尸源性人生长激素（c-hGH）。从1959年至1985年，英国至少有1848人接受了c-hGH治疗。但令人意想不到的是，c-hGH令部分患者得上了另外一种疾病，克雅病。克雅病是由错误折叠的PrP蛋白、也就是朊病毒引起的一种神经退行性疾病。朊病毒可诱发正常PrP的异常折叠，导致大脑的海绵样空洞。全世界范围内，已经发现200余例接受c-hGH治疗后患上医源性克雅病的病例，其中80余例来自英国。Collinge团队对这个课题非常关注。2015年，他们对8名死于克雅病的患者尸体进行了检查，这些人都曾在童年接受过c-hGH治疗。意外的是，除了克雅病的标志性病变，研究者们在其中4人的大脑中还发现了大量的Aβ沉积和脑血管Aβ病变（CAA）。这些患者的年龄在36-52岁之间，对于AD来说可算相当年轻，正常人在这一年龄段存在大量Aβ沉积的概率不到4%。幸运的是，当年这些患者使用过的c-hGH在英国卫生部门还有留样。由于当年使用的制备技术并不能消除垂体提取物中的异常蛋白，这些c-hGH中含有会导致克雅病朊病毒、也有AD相关的Aβ。2018年，Collinge团队在《自然》杂志发表论文，证实了AD相关Aβ可以像种子一样诱发正常小鼠大脑内的Aβ沉积。令人惊讶的是，常温下保存了30余年的c-hGH，其中的Aβ依旧稳定，可以诱发小鼠大脑Aβ沉积。在这之后，Collinge团队持续收集c-hGH相关报告，在2017年-2022年间又获取了8个有c-hGH治疗史的病例，这8位患者均非医源性克雅病，其中5人有显著的早发性痴呆症状。8名患者中，患者2/3/4/5/8的症状与早发性痴呆一致，在多个领域出现进行性认知障碍，严重影响日常生活。患者3/4/5/8症状发作于38-49岁之间，患者2症状发作在55岁。患者3/4/8已经诊断为AD，4/8有典型的遗忘症状并符合NIA-AA的诊断标准，3表现为非遗忘的语言症状。其余两例患者也符合NIA-AA对疑似AD的诊断标准。5人均符合DSM V对AD所致主要神经认知障碍的标准。其余3人中，患者1在42岁出现了符合NIA-AA定义的轻度认知障碍症状，患者7仅有主观认知症状，患者6无症状。8名患者特征患者3的MRI和PET影响，可见双侧颞叶显著萎缩患者1/4/5没有可用样本，研究者对其他5名患者进行了基因测序。患者2检测出了淀粉样蛋白前体蛋白基因（app）的意义不明变异（NM_000484.3：c.1486A>C; p.Lys496Gln），良性可能性较大；仅有患者2携带APOE4等位基因。其他的ABCA7、SORL1和TREM2等AD相关风险基因均未检出。虽然没有患者1/4/5的遗传数据，但是他们并没有早发性痴呆或中风（可能与CAA有关）的家族病史，可以认为他们并非家族性AD基因的携带者。也就是说，虽然这些患者表现与早发性AD相当一致，但他们却并未携带早发性AD基因。考虑到他们都很年轻，研究者认为他们的AD症状是由童年接受的c-hGH中的Aβ引发的，这是患者之间的唯一共性。有趣的是，这几例患者的表现与散发性AD和家族性AD都不完全符合，研究者认为这可能是医源性疾病的固有特征。这项研究仅涉及8个样本，规模较小，也有学者对其是否能够确证Aβ种子推动AD进展表示质疑。至少从公共卫生的角度，c-hGH治疗已经不复存在，我们无需担心相关的“传染”问题。但同时也需要关注外科手术等带来医源性传染风险。参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41591-023-02729-2[2]https://www-nature-com.libproxy1.nus.edu.sg/articles/d41586-024-00268-5本文作者丨代丝雨

*仅供医学专业人士阅读参考阿尔茨海默病（AD）的病理特征包括大脑中的β-淀粉样蛋白沉积和tau蛋白纤维缠结，即当前药物研发的两个重点方向。就在本月初，仑卡奈单抗在中国获批上市，成为首款在国内上市的治疗阿尔茨海默病的抗Aβ药物。但是越来越多的研究表明，AD的发病机制复杂，具有异质性，如果仅仅集中火力攻于β-淀粉样蛋白沉淀和tau蛋白异常，不同患者的临床获益可能会有很大差异。荷兰阿姆斯特丹自由大学的Betty M. Tijms等人通过对609名参与者的脑脊液进行蛋白质组学分析，揭示5种AD分子亚型。这些亚型分别以神经元增生、先天免疫异常激活、RNA失调、脉络丛功能障碍和血脑屏障功能障碍为特点，具有不同的遗传特征、临床结局、生存时间以及脑皮质萎缩特征[1]。这项研究成果强调了AD个体化治疗的重要性，文章于近日发表在《自然·衰老》期刊上。 论文首页 脑脊液环绕在大脑和脊髓周围，充当缓冲和保护作用，同时也参与营养物质和废物的运输。位置上的接近，使得脑脊液中的成分变化能够直接反映大脑的健康状况。 2020年，Betty M. Tijms等人基于脑脊液蛋白质组学确定了3种AD分子亚型[2]。如今蛋白质组学技术日益改进，研究者们认为是时候对AD亚型的描述进行完善。 此次，他们共获取609名参与者的脑脊液样本。其中419人经生物标志物检测诊断为不同阶段的AD患者，包括认知正常、轻度认知障碍（MCI）、痴呆症；其他人具有正常认知能力且未被诊断为AD。 总体来看，有1058种脑脊液蛋白质在非AD患者与AD患者之间差异表达。 研究者们进一步采用非负矩阵分解（NMF）的方法来对AD患者进行聚类分析，从而根据脑脊液蛋白质组学特征将AD患者分为5种亚型。 5种亚型的脑脊液蛋白质组学特征 亚型1的特点为神经元增生。表达上调的蛋白质与神经元可塑性相关，如突触组装、轴突引导、神经元生成、胶质细胞生成等生理过程。与其相关的AD遗传变异是TREM2 R47H。 亚型2的特点为先天免疫异常激活。显示小胶质细胞特异性蛋白水平升高，与先天免疫激活有关。与其相关的AD遗传变异是IDUA、CLNK和SCIMP。 亚型3的特点为RNA失调（RNA dysregulation）。表达上调的蛋白质参与细胞骨架组成、轴突运输、蛋白酶体功能、蛋白质折叠，尤其是异质核核糖核蛋白（hnRNP）等RNA结合蛋白，表达明显上调。与其相关的AD遗传变异是BIN1、TREM2 R62H、SPDYE3、SNX1、KAT8。 亚型4的特点为脉络丛（产生脑脊液的地方）功能障碍。表达上调的蛋白质中有45%参与脉络丛发育，涉及细胞粘附、SMAD通路；此外还有小胶质细胞等免疫细胞特异性蛋白水平升高。与其相关的AD遗传变异是ABCA7、PICALM、IL-34、CLNK。 亚型5的特点为血脑屏障功能障碍。白蛋白、纤维蛋白原、纤溶酶原和凝血酶等本不该存在于大脑的蛋白质，在这类亚型患者的脑脊液中水平异常升高，表明来自血液的蛋白质趁血脑屏障受损渗入大脑；与血液凝固、B细胞介导的免疫反应、急性炎症反应等生理过程相关的蛋白质表达上调。与其相关的AD遗传变异是IL-34、ECHDC3、APP。 其中，亚型1、2、3患者的脑脊液tau蛋白水平显著升高，而亚型4、5患者的脑脊液tau蛋白水平大多为正常。 相比于对照组，所有AD亚型的APOE e4基因变异水平、AD多基因风险评分（PRS）均更高。亚型5的APOE e4基因变异携带者比例为最高。 不同亚型由MCI进展痴呆症的风险不同，亚型2、5的风险最高，亚型4的风险最低。 不同亚型的生存情况不同，亚型3患者的平均生存时间最短，为5.6年；亚型1患者的平均生存时间最长，为8.9年。 此外，磁共振成像（MRI）扫描结果显示，不同亚型的脑皮质萎缩程度。与亚型1、2、5相比，亚型2、4具有更严重的脑皮质萎缩现象。 5种亚型的MRI图像和临床结局 最后，研究者们利用来自欧洲、美国等多个不同国家的多组队列进行验证，通过脑脊液蛋白质组学鉴定其AD亚型。结果观察到，与上面的发现队列中的比例相近，27.9%的AD患者为亚型1，35.5%为亚型2，5.8%为亚型3，17.1%为亚型4，16.6%为亚型5，且特征相符。 多国大型队列中验证5种AD亚型 这些结果意味着，基于脑脊液确定患者AD亚型或有助于选择个体进行特定的治疗。例如，亚型1的患者可能受益于针对TREM2的治疗，亚型2需要先天免疫抑制剂，亚型3需要恢复RNA功能，亚型4可能从抑制单核细胞浸润中受益，而亚型5需要针对脑血管的治疗[3]。 同时，某些治疗产生的副作用也可能取决于亚型。例如在抗体治疗，虽然抗体可能更容易穿过亚型5患者的血脑屏障，但这些人发生脑出血的风险也会增加[3]。 总之，提到AD，我们总会下意识将其认定为单一一种疾病进行治疗。而这项研究不仅揭示了AD在分子层面的复杂性，也为AD的个性化医疗提供了新的视角。随着研究的深入，我们有望更好地理解AD的复杂机制，并为患者提供更有效的治疗方案。 参考文献：[1]Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43587-023-00550-7[2]Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, Kilpert F, Ten Kate M, Barkhof F, Tsolaki M, Verhey FRJ, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Molinuevo JL, Engelborghs S, Bertram L, Lovestone S, Streffer J, Vos S, Bos I; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Blennow K, Scheltens P, Teunissen CE, Zetterberg H, Visser PJ. Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics. Brain. 2020 Dec 1;143(12):3776-3792. doi: 10.1093/brain/awaa325本文作者丨张艾迪

Alzheimer’s disease is the most common type of dementia, a disorder of progressively worsening memory and other thinking abilities. It rose up in the ranks of leading causes of death over the past several decades. It can also limit the duration of a working career, create uncertainty in the financial planning for retirement and rob patients of enjoyment and happiness in the final years. An effective treatment against this disease could give back to the patient the decision when to retire and improve quality of life in advanced age.   Now, scientists are on the trail of a promising new therapeutic target – ABCA7, a protein known to protect from Alzheimer’s disease. The study uncovers new information about the relationship between ABCA7, cholesterol, and inflammation in human brain cells. Alzheimer's disease is the most common type of dementia, a disorder of progressively worsening memory and other thinking abilities. It rose up in the ranks of leading causes of death over the past several decades. It can also limit the duration of a working career, create uncertainty in the financial planning for retirement and rob patients of enjoyment and happiness in the final years. An effective treatment against this disease could give back to the patient the decision when to retire and improve quality of life in advanced age. Now, scientists at the Alzheimer's Center at Temple at the Lewis Katz School of Medicine at Temple University are on the trail of a promising new therapeutic target -- ABCA7, a protein known to protect from Alzheimer's disease. The study, published online in the journal Cells, uncovers new information about the relationship between ABCA7, cholesterol, and inflammation in human brain cells. The importance of ABCA7 in the development of Alzheimer's disease first emerged in genome-wide association studies, which are large investigations of the human genome that involve thousands of participants. "But genome studies only point to a protein and do not tell us anything about how it functions or how it affects a disease," said Joel Wiener, an investigator with the Alzheimer's Center at Temple and first author on the new report. "Our goal is to reveal ABCA7's functions and to use what we learn about its role in pathology to turn it into an effective therapy against Alzheimer's disease." Previous work led by Nicholas Lyssenko, PhD, an investigator at the Alzheimer's Center at Temple and corresponding author on the new study, suggested that individuals between ages 63 and 78 who have low ABCA7 protein levels in the brain are at a greater risk of developing Alzheimer's disease. This finding corroborated the conclusions of earlier genome studies and further indicated that the protein protects the human brain. In the new study, Dr. Lyssenko's team addressed how cholesterol metabolism and inflammation may manipulate ABCA7 levels in human brain cells and thus affect Alzheimer's disease pathogenesis. In one set of experiments, the researchers depleted cholesterol in different neural cell lines, such as microglia, astrocytes and neurons, and then treated the cells with rosuvastatin, a medication that suppresses cholesterol synthesis. To determine the effect of inflammation on ABCA7, the team carried out another set of experiments in which the same cell lines were treated with one of three major proinflammatory cytokines: IL-1β, IL-6, or TNFα. Cytokines are small molecules that can trigger inflammation following their secretion from certain types of immune cells. The researchers found that ABCA7 levels dropped by about 40 percent in microglia cell lines and about 20 percent in an astrocyte cell line after the cells were depleted of more than half their usual amount of cholesterol. Meanwhile, no changes were observed in ABCA7 levels in a neuronal cell line following cholesterol loss. In addition, IL-1β and TNFα suppressed ABCA7 expression only in microglial cells. The third cytokine, IL-6, had no impact on ABCA7 in microglia, and none of the three cytokines induced changes in ABCA7 levels in either astrocytes or neurons. These observations advance understanding of how ABCA7 is regulated in the brain. "Our findings suggest that cholesterol loss downregulates ABCA7 in many cells in the human brain. Previous work in mice showed that cholesterol loss upregulates ABCA7," said Mr. Wiener. "In addition, other investigators found that inflammation suppresses ABCA7 in astrocytes, and we show now that this can also happen in microglia. Overall, cholesterol depletion and inflammation may reduce ABCA7 levels in the brain and cause the onset of Alzheimer's disease." The Temple team is taking multiple approaches to studying ABCA7, using not only human cells but also carrying out experiments in animal models and in postmortem human brain tissue. "The greatest challenge now is to figure out how to measure ABCA7 levels in the brain of living humans," Dr. Lyssenko added. "If we achieve this, we could verify whether inflammation suppresses ABCA7 in the human body. Effective testing for ABCA7 levels in the brain will also identify individuals who are at greater risk for Alzheimer's disease and spur the development of new ABCA7-based therapies." Other researchers who contributed to the study include Sindy Desire, Viktor Garliyev, Nicholas Lyssenko III, and Domenico Praticò, Alzheimer's Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine. The research was supported by funding from the National Institute on Aging at the National Institutes of Health (NIH) and from the Pennsylvania Department of Health, Commonwealth Universal Research Enhancement Program.