Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
Alzheimers Dement. 2023 Nov;19(11):4872-4885. doi: 10.1002/alz.13058. Epub 2023 Apr 10.
Sporadic Alzheimer's disease (sAD) is the leading type of dementia. Brain glucose hypometabolism, along with decreased O-GlcNAcylation levels, occurs before the onset of symptoms and correlates with pathogenesis. Heretofore, the mechanisms involved and the roles of O-GlcNAcylation in sAD pathology largely remain unknown due to a lack of human models of sAD.
Human cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media.
We found a narrow window of glucose concentration that induces sAD-like phenotypes in PSC-derived neurons. With our model, we reveal that dysregulated O-GlcNAc, in part through mitochondrial dysfunction, causes the onset of sAD-like changes. We demonstrate the therapeutic potential of inhibiting O-GlcNAcase in alleviating AD-like biochemical changes.
Our results suggest that dysregulated O-GlcNAc might be a direct molecular link between hypometabolism and sAD-like alternations. Moreover, this model can be exploited to explore molecular processes and for drug development.
Lowering glucose to a critical level causes AD-like changes in cortical neurons. Defective neuronal structure and function were also recapitulated in current model. Dysregulated O-GlcNAcylation links impaired glucose metabolism to AD-like changes. Mitochondrial abnormalities correlate with O-GlcNAcylation and precede AD-like phenotype. Our model provides a platform to study sAD as a metabolic disease in human neurons.
散发性阿尔茨海默病（sAD）是主要的痴呆类型。在症状出现之前，大脑葡萄糖代谢低下以及 O-GlcNAc 水平降低与发病机制相关。迄今为止，由于缺乏 sAD 的人类模型，因此尚不清楚涉及的机制以及 O-GlcNAc 化在 sAD 病理学中的作用。
从多能干细胞（PSC）中生成人皮质神经元，并进行葡萄糖还原介质处理。
我们发现葡萄糖浓度的狭窄窗口可诱导 PSC 衍生神经元中出现 sAD 样表型。通过我们的模型，我们发现失调的 O-GlcNAc 部分通过线粒体功能障碍导致 sAD 样变化的发生。我们证明了抑制 O-GlcNAcase 在缓解 AD 样生化变化中的治疗潜力。
我们的结果表明，失调的 O-GlcNAc 可能是代谢低下与 sAD 样改变之间的直接分子联系。此外，该模型可用于探索分子过程和药物开发。
将葡萄糖降低到临界水平会导致皮质神经元出现 AD 样变化。当前模型中也再现了神经元结构和功能的缺陷。失调的 O-GlcNAcylation 将葡萄糖代谢受损与 AD 样变化联系起来。线粒体异常与 O-GlcNAc 化相关，并先于 AD 样表型出现。我们的模型为在人类神经元中研究 sAD 作为代谢疾病提供了一个平台。
