Gaire Bhakta Prasad, Koronyo Yosef, Vit Jean-Philippe, Hutton Alexandre, Swerdlow Natalie, Fuchs Dieu-Trang, Rentsendorj Altan, Shahin Saba, Subedi Lalita, Robinson Edward, Ljubimov Alexander V, Schneider Lon S, Hawes Debra, Graham Stuart L, Gupta Vivek K, Mirzaei Mehdi, Black Keith L, Meyer Jesse G, Arditi Moshe, Crother Timothy R, Koronyo-Hamaoui Maya
Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
bioRxiv. 2025 Jun 25:2025.06.19.660619. doi: 10.1101/2025.06.19.660619.
(Cp), an obligate intracellular bacterium, has been implicated in Alzheimer's disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.1-fold increases in Cp inclusions in AD retinas and brains, with no significant elevation in mild cognitive impairment (MCI). Proteomics revealed dysregulation of retinal and brain bacterial infection-related proteins and NLRP3 inflammasome pathways. NLRP3 expression was markedly elevated in MCI and AD retinas, and its activation was evident by increased N-terminal gasdermin D (NGSDMD) and mature interleukin-1β. Retinal Cp strongly correlated with Aβ and NLRP3 inflammasome components, which tightly linked to cleaved caspase-3-apoptotic and NGSDMD-pyroptotic cell death. Although retinal microgliosis was elevated in AD, Cp-associated microglia were reduced by 62%, suggesting impaired Cp phagocytosis. Higher retinal Cp burden correlated with APOEε4, Braak stage, and cognitive deficit. Machine learning identified retinal Cp or NLRP3 combined with Aβ as strong predictors of AD diagnosis, staging, and cognitive impairment. Our findings suggest that Cp infection contributes to AD dementia but not initiating pathology, whereas early NLRP3 activation may promote disease development, warranting studies on Cp's role in AD pathogenesis and early antibiotic or inflammasome-targeted therapies.
嗜肺军团菌（Cp）是一种专性胞内细菌，与阿尔茨海默病（AD）有关，但其在视网膜病理学中的作用仍未得到探索。我们分析了95名人类供体的尸检组织，发现AD视网膜和大脑中Cp包涵体增加了2.9至4.1倍，而轻度认知障碍（MCI）中无显著升高。蛋白质组学揭示了视网膜和大脑细菌感染相关蛋白以及NLRP3炎性小体途径的失调。NLRP3在MCI和AD视网膜中的表达显著升高，其激活通过N端gasdermin D（NGSDMD）和成熟白细胞介素-1β的增加而明显。视网膜Cp与Aβ和NLRP3炎性小体成分密切相关，这些成分与裂解的半胱天冬酶-3凋亡和NGSDMD焦亡细胞死亡紧密相连。尽管AD中视网膜小胶质细胞增生增加，但与Cp相关的小胶质细胞减少了62%，表明Cp吞噬受损。较高的视网膜Cp负荷与APOEε4、Braak分期和认知缺陷相关。机器学习确定视网膜Cp或NLRP3与Aβ结合是AD诊断、分期和认知障碍的强预测指标。我们的研究结果表明，Cp感染导致AD痴呆，但不是引发病理学，而早期NLRP3激活可能促进疾病发展，这为研究Cp在AD发病机制中的作用以及早期抗生素或炎性小体靶向治疗提供了依据。
