López-Cepeda Misael Leonardo, Angarita-Rodríguez Andrea, Rojas-Cruz Alexis Felipe, Pérez Mejia Julián, Khatri Robin, Brehler Michael, Martínez-Martínez Eduardo, Pinzón Andrés, Aristizabal-Pachon Andrés Felipe, González Janneth
Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá 110231, Colombia.
Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá 111321, Colombia.
Int J Mol Sci. 2025 Apr 9;26(8):3544. doi: 10.3390/ijms26083544.
Extracellular vesicles (EVs) are small capsular bodies released by cells, mediating responses in intercellular communication. The role of EVs in Aβ pathology spreading in the Alzheimer's disease (AD) brain has been evidenced, although whether this occurs due to the co-transportation of Aβ peptides or contribution of other factors, such as EV-associated transcripts, remains uncertain. In vitro studies of miRNA cargo in neuron-derived extracellular vesicles (NDEVs) show that Aβ hyperexpression alters the transcriptomic profile; however, it is not clear to what extent this causes changes at the organ level. By utilizing datasets from published studies, we generated competing endogenous RNA (ceRNA) networks for miRNAs co-expressed in NDEVs and the brain in different stages of pathology, using both an APP overexpressing neuronal model (in vitro) and brain cortices from 6- and 9-month-old APP/PSEN1 mice (in vivo). Networks integrating information from mRNAs, lncRNAs, and circRNAs showed two candidate lncRNAs (Kcnq1ot1 and Gm42969) and a circRNA (Pum1), while enrichment analyses detected that NDEVs miRNAs signal to other CNS cells and that this signal can be disrupted by Aβ pathology, contributing to the loss of long-term potentiation seen in early AD.
细胞外囊泡（EVs）是细胞释放的小囊泡体，介导细胞间通讯中的反应。EVs在阿尔茨海默病（AD）大脑中Aβ病理传播中的作用已得到证实，尽管这是由于Aβ肽的共同运输还是其他因素（如EV相关转录本）的作用尚不确定。对神经元衍生的细胞外囊泡（NDEVs）中miRNA货物的体外研究表明，Aβ过表达会改变转录组谱；然而，尚不清楚这在多大程度上会在器官水平上引起变化。通过利用已发表研究的数据集，我们使用过表达APP的神经元模型（体外）和6个月及9个月大的APP/PSEN1小鼠的大脑皮质（体内），为NDEVs和不同病理阶段大脑中共同表达的miRNA生成了竞争性内源RNA（ceRNA）网络。整合来自mRNA、lncRNA和circRNA信息的网络显示了两个候选lncRNA（Kcnq1ot1和Gm42969）和一个circRNA（Pum1），而富集分析检测到NDEVs miRNA向其他中枢神经系统细胞发出信号，并且该信号会被Aβ病理破坏，导致早期AD中出现的长时程增强的丧失。
