Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Hum Mol Genet. 2022 Mar 31;31(7):1022-1034. doi: 10.1093/hmg/ddab285.
The purpose of our study is to determine DDQ (diethyl (3,4-dihydroxyphenethylamino) (quinolin-4-yl) methylphosphonate)-a newly discovered molecule that has been shown to protect against phosphorylated tau (p-tau) in Alzheimer's disease (AD) pathogenesis. We used a well-studied tau (P301L) transgenic mouse model to achieve our goal. We administered DDQ into 12-month-old Tau mice, at 20 mg/kg body weight intraperitoneally two times per week for 2 months. We also assessed DDQ levels in the blood, skeletal muscle and brain using biochemical and molecular techniques. We investigated the mRNA and protein levels of mitochondrial dynamics, biogenesis, synaptic, p-tau and longevity genes sirtuins in DDQ-treated tau mice using real-time quantitative PCR (q-RT-PCR), immunoblotting and immunofluorescence techniques. Our extensive pharmacodynamics investigations revealed that skeletal muscle had the greatest peak levels of DDQ, followed by serum and brain. Interestingly, DDQ-treated tau mice had higher levels of mitochondrial fusion, biogenesis, synaptic genes and sirtuins than DDQ-untreated tau mice. In addition, DDQ-treated tau mice had lower levels of mitochondrial fission and p-tau than untreated tau mice. The current findings, combined with our prior findings, firmly show that DDQ possesses anti-aging, anti-amyloid-beta and anti-p-tau properties, making it a promising molecule for reducing age-related, amyloid-beta and p-tau-induced synaptic and mitochondrial toxicities in AD.
我们研究的目的是确定 DDQ（二乙基（3,4-二羟基苯乙基氨基）（喹啉-4-基）甲基膦酸酯），这是一种新发现的分子，已被证明可预防阿尔茨海默病（AD）发病机制中的磷酸化 tau（p-tau）。我们使用了一种经过充分研究的 tau（P301L）转基因小鼠模型来实现我们的目标。我们以 20mg/kg 体重的剂量通过腹腔内注射的方式每周两次给 12 个月大的 Tau 小鼠施用 DDQ，持续两个月。我们还使用生化和分子技术评估了 DDQ 在血液、骨骼肌和大脑中的水平。我们使用实时定量 PCR（q-RT-PCR）、免疫印迹和免疫荧光技术研究了 DDQ 处理的 tau 小鼠中线粒体动力学、生物发生、突触、p-tau 和长寿基因 sirtuins 的 mRNA 和蛋白水平。我们的广泛药效学研究表明，骨骼肌具有最大的 DDQ 峰值水平，其次是血清和大脑。有趣的是，与未用 DDQ 处理的 tau 小鼠相比，DDQ 处理的 tau 小鼠具有更高水平的线粒体融合、生物发生、突触基因和 sirtuins。此外，与未用 tau 处理的 tau 小鼠相比，DDQ 处理的 tau 小鼠具有更低水平的线粒体裂变和 p-tau。目前的研究结果与我们之前的研究结果相结合，有力地表明 DDQ 具有抗衰老、抗淀粉样β和抗 p-tau 的特性，使其成为一种有前途的分子，可以减少 AD 中与年龄相关的、淀粉样β和 p-tau 诱导的突触和线粒体毒性。
