Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA.
Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
Genes (Basel). 2024 Apr 28;15(5):569. doi: 10.3390/genes15050569.
Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's Disease and Related Dementias (ADRD) accounts for nearly 60-70% of all those cases. The spread of Alzheimer's Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD's causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs' ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated statistics FDR-corrected -value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs' transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 () gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.
目前，全球有超过 5500 万人患有痴呆症，其中阿尔茨海默病和相关痴呆症（ADRD）占所有病例的近 60-70%。阿尔茨海默病（AD）病理和海马和大脑皮层中进行性神经退行性变的传播与 AD 患者的认知能力下降密切相关；然而，ADRD 因果关系的分子基础仍不清楚。对 AD 尸检大脑和 AD 动物模型的研究表明，升高的内质网（ER）应激可能通过改变与学习和记忆相关的脑区的神经细胞内稳态，在 ADRD 病理中发挥作用。为了研究 ER 应激相关的神经细胞反应及其对神经细胞内稳态和神经发生的影响，我们使用 thapsigargin（TG）在我们的墨西哥裔美国人家庭研究（MAFS）中的两个人的诱导多能干细胞（iPSC）衍生的神经干细胞（NSC）中模拟 ER 应激挑战。对对照和 ER 应激挑战的 NSC 的高内涵筛选和转录组分析表明，NSC 的 ER 应激反应导致 NSC 自我更新显着下降，细胞凋亡和细胞氧化应激增加。共有 2300 个基因显着（调节统计学 FDR 校正 - 值≤0.05，倍数变化绝对值≥2.0）差异表达（DE）。差异表达基因的通路富集和基因网络分析表明，所有三种未折叠蛋白反应（UPR）途径，蛋白激酶 RNA 样内质网激酶（PERK），激活转录因子-6（ATF-6）和肌醇需求酶-1（IRE1）均显着激活并协同调节 NSC 对 ER 应激的转录反应。我们的研究结果表明，IRE1 / X 盒结合蛋白 1（XBP1）介导 E2F 转录因子 1（）基因的转录调节，其下游靶基因在 ER 应激挑战的 NSC 中诱导 G1 / S 期细胞周期阻滞中起主导作用。ER 应激挑战的 NSC 还显示出 C / EBP 同源蛋白（CHOP）介导的细胞凋亡的激活以及与突触可塑性和神经递质稳态相关基因的失调。总体而言，我们的研究结果表明，NSC 自我更新的减弱、凋亡增加以及突触可塑性和神经递质稳态失调可能在 ADRD 的发病机制中起作用。
