美国艾伦脑科学研究所Ed S. Lein等研究人员合作绘制出阿尔茨海默病的综合多模态细胞图谱。这一研究成果于2024年10月14日在线发表在国际学术期刊《自然—神经科学》上。

研究人员利用多组学、空间基因组学以及来自BRAIN计划的参考图谱，研究了84位具有不同阿尔茨海默病（AD）病理的捐赠者的中颞回细胞类型。该研究队列包括33位男性捐赠者和51位女性捐赠者，死亡时的平均年龄为88岁。研究人员通过定量神经病理学将捐赠者置于疾病伪进展评分上。

伪进展分析揭示了疾病的两个阶段：早期阶段，病理逐渐增加，存在炎性小胶质细胞、反应性星形胶质细胞、抑制性神经元中的生长抑素阳性细胞丢失，以及由少突胶质前体细胞引发的再髓鞘化反应。晚期阶段，病理呈指数增加，兴奋性神经元以及Pvalb⁺和Vip⁺抑制性神经元亚型的丢失。这些发现也在其他主要的AD研究中得到了验证。

据了解，AD是老年人痴呆的主要原因。尽管AD的进展以蛋白质病的逐步积累为特征，但受影响的细胞群体仍未得到充分研究。

附：英文原文

Title: Integrated multimodal cell atlas of Alzheimer’s disease

Author: Gabitto, Mariano I., Travaglini, Kyle J., Rachleff, Victoria M., Kaplan, Eitan S., Long, Brian, Ariza, Jeanelle, Ding, Yi, Mahoney, Joseph T., Dee, Nick, Goldy, Jeff, Melief, Erica J., Agrawal, Anamika, Kana, Omar, Zhen, Xingjian, Barlow, Samuel T., Brouner, Krissy, Campos, Jazmin, Campos, John, Carr, Ambrose J., Casper, Tamara, Chakrabarty, Rushil, Clark, Michael, Cool, Jonah, Dalley, Rachel, Darvas, Martin, Ding, Song-Lin, Dolbeare, Tim, Egdorf, Tom, Esposito, Luke, Ferrer, Rebecca, Fleckenstein, Lynn E., Gala, Rohan, Gary, Amanda, Gelfand, Emily, Gloe, Jessica, Guilford, Nathan, Guzman, Junitta, Hirschstein, Daniel, Ho, Windy, Hupp, Madison, Jarsky, Tim, Johansen, Nelson, Kalmbach, Brian E., Keene, Lisa M., Khawand, Sarah, Kilgore, Mitchell D., Kirkland, Amanda, Kunst, Michael, Lee, Brian R., Leytze, Mckaila, Mac Donald, Christine L., Malone, Jocelin, Maltzer, Zoe, Martin, Naomi, McCue, Rachel, McMillen, Delissa, Mena, Gonzalo, Meyerdierks, Emma, Meyers, Kelly P., Mollenkopf, Tyler, Montine, Mark, Nolan, Amber L., Nyhus, Julie K., Olsen, Paul A., Pacleb, Maiya, Pagan, Chelsea M., Pea, Nicholas, Pham, Trangthanh, Pom, Christina Alice, Postupna, Nadia, Rimorin, Christine, Ruiz, Augustin, Saldi, Giuseppe A.

Issue&Volume: 2024-10-14

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.

DOI: 10.1038/s41593-024-01774-5

Source: https://www.nature.com/articles/s41593-024-01774-5