Daoutsali Elena, Pepers Barry A, Stamatakis Stavros, van der Graaf Linda M, Terwindt Gisela M, Parfitt David A, Buijsen Ronald A M, van Roon-Mom Willeke M C
Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
Front Aging Neurosci. 2023 Jan 17;14:1048584. doi: 10.3389/fnagi.2022.1048584. eCollection 2022.
ADutch-type cerebral amyloid angiopathy (D-CAA) is a hereditary brain disorder caused by a point mutation in the amyloid precursor protein (APP) gene. The mutation is located within the amyloid beta (Aβ) domain of APP and leads to Aβ peptide accumulation in and around the cerebral vasculature. There lack of disease models to study the cellular and molecular pathological mechanisms of D-CAA together with the absence of a disease phenotype in vitro in overexpression cell models, as well as the limited availability of D-CAA animal models indicates the need for a D-CAA patient-derived model.
We generated cerebral organoids from four D-CAA patients and four controls, cultured them up to 110 days and performed immunofluorescent and targeted gene expression analyses at two time points (D52 and D110).
D-CAA cerebral organoids exhibited Aβ accumulations, showed enhanced neuronal and astrocytic gene expression and TGFβ pathway de-regulation.
These results illustrate the potential of cerebral organoids as in vitro disease model of D-CAA that can be used to understand disease mechanisms of D-CAA and can serve as therapeutic intervention platform for various Aβ-related disorders.
荷兰型脑淀粉样血管病（D-CAA）是一种由淀粉样前体蛋白（APP）基因点突变引起的遗传性脑部疾病。该突变位于APP的淀粉样β（Aβ）结构域内，导致Aβ肽在脑血管系统及其周围积聚。由于缺乏研究D-CAA细胞和分子病理机制的疾病模型，以及过表达细胞模型中缺乏体外疾病表型，再加上D-CAA动物模型的可用性有限，表明需要一种源自D-CAA患者的模型。
我们从四名D-CAA患者和四名对照者中生成了脑类器官，将它们培养长达110天，并在两个时间点（第52天和第110天）进行免疫荧光和靶向基因表达分析。
D-CAA脑类器官表现出Aβ积聚，神经元和星形胶质细胞基因表达增强，TGFβ信号通路失调。
这些结果说明了脑类器官作为D-CAA体外疾病模型的潜力，可用于了解D-CAA的疾病机制，并可作为各种Aβ相关疾病的治疗干预平台。
