Batra Richa, Krumsiek Jan, Wang Xue, Allen Mariet, Blach Colette, Kastenmüller Gabi, Arnold Matthias, Ertekin-Taner Nilüfer, Kaddurah-Daouk Rima
Department of Physiology and Biophysics, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York, USA.
Department of Quantitative Health Sciences, Mayo Clinic Florida, Jacksonville, Florida, USA.
Alzheimers Dement. 2024 Dec;20(12):8294-8307. doi: 10.1002/alz.14249. Epub 2024 Oct 22.
Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed.
We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies.
Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B.
Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP.
First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences.
代谢失调是神经退行性疾病的一个标志，包括阿尔茨海默病（AD）和进行性核上性麻痹（PSP）。尽管代谢失调是这两种tau蛋白病之间的一个共同联系，但尚未对这两种疾病进行全面的脑代谢比较。
我们分析了梅奥诊所脑库的342份尸检脑样本，并检测了这两种tau蛋白病的小脑皮质和颞叶皮质中的658种代谢物。
我们的研究结果表明，这两种疾病均表现出与脂质代谢相关的氧化应激、与赖氨酸代谢相关的线粒体功能障碍，以及tau诱导的多胺应激反应迹象。然而，AD特有的表现为，我们检测到与谷胱甘肽相关的神经炎症、与嘌呤相关的酶的失调，以及与维生素B相关的认知缺陷。
我们的研究结果强调了大脑代谢组的巨大变化，揭示了AD和PSP中共同的神经退行性途径和疾病特异性特征。
首次对脑组织中的阿尔茨海默病（AD）与进行性核上性麻痹（PSP）进行高通量代谢比较。尽管小脑皮质（CER）的蛋白病变有限，但显示出与AD相关的大量代谢变化。AD影响CER和颞叶皮质（TCX）；PSP的变化主要在CER。尽管存在主要的病理差异，但AD和PSP存在共同的代谢改变。
