Sonsungsan Pajaree, Aimauthon Supatha, Sriwichai Nattawet, Namchaiw Poommaree
Mathematics and Statistics, School of Science, Walailak University, Nakhon Si Thammarat, Thailand.
Chemical Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
Heliyon. 2024 Oct 15;10(20):e39378. doi: 10.1016/j.heliyon.2024.e39378. eCollection 2024 Oct 30.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by symptoms such as memory loss and impaired learning. This study conducted a cross-transcriptomic analysis of AD using existing microarray datasets from the hippocampus (HC) and entorhinal cortex (EC), comparing them with age-matched non-AD controls. Both of these brain regions are critical for learning and memory processing and are vulnerable areas that exhibit abnormalities in early AD. The cross-transcriptomic analysis identified 564 significantly differentially expressed genes in HC and 479 in EC. Among these, 151 genes were significantly differentially expressed in both tissues, with functions related to synaptic vesicle clustering, synaptic vesicle exocytosis/endocytosis, mitochondrial ATP synthesis, hydrogen ion transmembrane transport, and structural constituent of cytoskeleton, suggesting a potential association between cognitive decline in AD, synaptic vesicle dynamics, dysregulation of cytoskeleton organization, and mitochondrial dysfunction. Further gene ontology analysis specific to the HC revealed the gene ontology enrichment in aerobic respiration, synaptic vesicle cycle, and oxidative phosphorylation. The enrichment analysis in CA1 of HC revealed differentiation in gene expression related to mitochondrial membrane functions involved in bioenergetics, mitochondrial electron transport, and biological processes associated with microtubule-based process, while analysis in the EC region showed enrichment in synaptic vesicle dynamics which is associated with neurotransmitter release and the regulation of postsynaptic membrane potential and synaptic transmission of GABAergic and glutamatergic synapse. Protein-protein interaction analysis highlighted central hub proteins predominantly expressed in mitochondria, involved in regulation of oxidative stress and ATP synthesis. These hub proteins interact not only within the mitochondria but also with proteins in the vesicular membrane and neuronal cytoskeleton, indicating a central role of mitochondria. This finding underscores the association between clinical symptoms and mitochondrial dysregulation of synaptic vesicle dynamics, cytoskeleton organization, and mitochondrial processes in both the HC and EC of AD. Therefore, targeting these dysregulated pathways could provide promising therapeutic targets aimed at cognitive decline and memory impairment in early AD stages.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征为记忆力丧失和学习能力受损等症状。本研究利用来自海马体（HC）和内嗅皮质（EC）的现有微阵列数据集对AD进行了交叉转录组分析，并将其与年龄匹配的非AD对照进行比较。这两个脑区对于学习和记忆处理都至关重要，并且是早期AD中出现异常的易损区域。交叉转录组分析在HC中鉴定出564个显著差异表达基因，在EC中鉴定出479个。其中，151个基因在两个组织中均显著差异表达，其功能与突触小泡聚集、突触小泡胞吐作用/内吞作用、线粒体ATP合成、氢离子跨膜运输以及细胞骨架的结构成分有关，这表明AD中的认知衰退、突触小泡动力学、细胞骨架组织失调和线粒体功能障碍之间可能存在关联。对HC进行的进一步基因本体分析揭示了有氧呼吸、突触小泡循环和氧化磷酸化方面的基因本体富集。HC的CA1区的富集分析揭示了与生物能量学中涉及的线粒体膜功能、线粒体电子传递以及与微管相关过程的生物过程相关的基因表达差异，而EC区域的分析显示突触小泡动力学方面的富集，这与神经递质释放以及GABA能和谷氨酸能突触的突触后膜电位调节和突触传递有关。蛋白质-蛋白质相互作用分析突出了主要在线粒体中表达的中心枢纽蛋白，这些蛋白参与氧化应激调节和ATP合成。这些枢纽蛋白不仅在线粒体内相互作用，还与囊泡膜和神经元细胞骨架中的蛋白相互作用，表明线粒体起着核心作用。这一发现强调了临床症状与AD的HC和EC中突触小泡动力学、细胞骨架组织和线粒体过程的线粒体失调之间的关联。因此，针对这些失调的途径可能会为早期AD阶段的认知衰退和记忆损害提供有前景的治疗靶点。
