Prinzi Chiara, Kostenko Anna, de Leo Gioacchino, Gulino Rosario, Leanza Giampiero, Caccamo Antonella
Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy.
B.R.A.I.N. (Basic Research and Integrative Neuroscience) Laboratory for Neurogenesis and Repair, Department of Life Sciences, University of Trieste, 34100 Trieste, Italy.
Biology (Basel). 2023 Sep 21;12(9):1264. doi: 10.3390/biology12091264.
Noradrenaline (NA) depletion occurs in Alzheimer's disease (AD); however, its relationship with the pathological expression of Tau and transactive response DNA-binding protein 43 (TDP-43), two major hallmarks of AD, remains elusive. Here, increasing doses of a selective noradrenergic immunotoxin were injected into developing rats to generate a model of mild or severe NA loss. At about 12 weeks post-lesion, dose-dependent working memory deficits were detected in these animals, associated with a marked increase in cortical and hippocampal levels of TDP-43 phosphorylated at Ser 409/410 and Tau phosphorylated at Thr 217. Notably, the total levels of both proteins were largely unaffected, suggesting a direct relationship between neocortical/hippocampal NA depletion and the phosphorylation of pathological Tau and TDP-43 proteins. As pTD43 is present in 23% of AD cases and pTau Thr217 has been detected in patients with mild cognitive impairment that eventually would develop into AD, improvement of noradrenergic function in AD might represent a viable therapeutic approach with disease-modifying potential.
去甲肾上腺素（NA）耗竭在阿尔茨海默病（AD）中会出现；然而，其与AD的两个主要标志——Tau蛋白和反式激活应答DNA结合蛋白43（TDP - 43）的病理表达之间的关系仍不清楚。在此，将递增剂量的选择性去甲肾上腺素能免疫毒素注射到发育中的大鼠体内，以建立轻度或重度NA缺失模型。在损伤后约12周，在这些动物中检测到剂量依赖性的工作记忆缺陷，这与丝氨酸409/410位点磷酸化的TDP - 43以及苏氨酸217位点磷酸化的Tau在皮质和海马中的水平显著增加有关。值得注意的是，这两种蛋白的总水平基本未受影响，表明新皮质/海马NA耗竭与病理性Tau蛋白和TDP - 43蛋白的磷酸化之间存在直接关系。由于pTD43在23%的AD病例中存在，并且在最终会发展为AD的轻度认知障碍患者中已检测到pTau Thr217，改善AD中的去甲肾上腺素能功能可能代表一种具有疾病修饰潜力的可行治疗方法。
