de la Monte Suzanne M, Tong Ming
Departments of Medicine, Pathology and Laboratory Medicine, Neurology, and Neurosurgery, Rhode Island Hospital, Women and Infants Hospital, The Alpert Medical School at Brown University, Providence, RI, United States.
Department of Medicine, Rhode Island Hospital, The Alpert Medical School at Brown University, Providence, RI, United States.
Front Cell Neurosci. 2024 Sep 25;18:1432359. doi: 10.3389/fncel.2024.1432359. eCollection 2024.
Beyond the signature amyloid-beta plaques and neurofibrillary tangles, Alzheimer's disease (AD) has been shown to exhibit dysregulated metabolic signaling through insulin and insulin-like growth factor (IGF) networks that crosstalk with the mechanistic target of rapamycin (mTOR). Its broad impact on brain structure and function suggests that mTOR is likely an important therapeutic target for AD.
This study characterizes temporal lobe (TL) mTOR signaling abnormalities in a rat model of sporadic AD neurodegeneration.
Long Evans rats were given intracerebroventricular injections of streptozotocin (ic-STZ) or saline (control), and 4 weeks later, they were administered neurobehavioral tests followed by terminal harvesting of the TLs for histopathological study and measurement of AD biomarkers, neuroinflammatory/oxidative stress markers, and total and phosphorylated insulin/IGF-1-Akt-mTOR pathway signaling molecules.
Rats treated with ic-STZ exhibited significantly impaired performance on Rotarod (RR) and Morris Water Maze (MWM) tests, brain atrophy, TL and hippocampal neuronal and white matter degeneration, and elevated TL pTau, AβPP, Aβ, AChE, 4-HNE, and GAPDH and reduced ubiquitin, IL-2, IL-6, and IFN-γ immunoreactivities. In addition, ic-STZ reduced TL -IGF-1R, Akt, PTEN, -PTEN, -mTOR, p70S6K, -p70S6K, p/T--p70S6K, p/T-Rictor, and p/T-Raptor.
Experimental ic-STZ-induced sporadic AD-type neurodegeneration with neurobehavioral dysfunctions associated with inhibition of mTOR signaling networks linked to energy metabolism, plasticity, and white matter integrity.
除了标志性的淀粉样β斑块和神经纤维缠结外，阿尔茨海默病（AD）已被证明通过与雷帕霉素机制靶点（mTOR）相互作用的胰岛素和胰岛素样生长因子（IGF）网络表现出代谢信号失调。其对脑结构和功能的广泛影响表明，mTOR可能是AD的一个重要治疗靶点。
本研究对散发性AD神经退行性变大鼠模型的颞叶（TL）mTOR信号异常进行了表征。
给Long Evans大鼠脑室内注射链脲佐菌素（ic-STZ）或生理盐水（对照），4周后，对它们进行神经行为测试，然后取其TL进行组织病理学研究，并测量AD生物标志物、神经炎症/氧化应激标志物以及胰岛素/IGF-1-Akt-mTOR通路信号分子的总量和磷酸化水平。
接受ic-STZ治疗的大鼠在转棒试验（RR）和莫里斯水迷宫试验（MWM）中表现出明显受损，出现脑萎缩、TL和海马神经元及白质变性，TL中pTau、AβPP、Aβ、AChE、4-HNE和GAPDH升高，泛素、IL-2、IL-6和IFN-γ免疫反应性降低。此外，ic-STZ降低了TL中的IGF-1R、Akt、PTEN、PTEN、mTOR、p70S6K、p70S6K、p/T-p70S6K、p/T-Rictor和p/T-Raptor。
实验性ic-STZ诱导的散发性AD型神经退行性变伴有与能量代谢、可塑性和白质完整性相关的mTOR信号网络抑制所导致的神经行为功能障碍。
