MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus.
MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, improves episodic memory, and reduces serum levels of tumor necrosis factor-alpha and neurodegeneration in mouse models of Type 1 and Type 2 Diabetes Mellitus.
复制标题
MA-[D-Leu-4]-OB3 是一种小分子合成肽瘦素模拟物，可改善 1 型和 2 型糖尿病小鼠模型的情景记忆，降低肿瘤坏死因子-α 的血清水平和神经变性。
DOI：
10.1016/j.bbagen.2020.129697
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Grasso,Patricia
中科院分区：
文献类型：
--
作者：
Hirschstein,Zall;Vanga,GautamReddy;Wang,Guirong;Novakovic,ZacharyM;Grasso,Patricia
胞外β -淀粉样蛋白（Aβ）、神经元内过度磷酸化的tau蛋白和慢性炎症是阿尔茨海默病（AD）的神经病理学标志。AD、胰岛素功能障碍和肿瘤坏死因子-α (TNF-α)在体内促进tau和Aβ病理之间存在联系。方法将sma -[D-Leu-4]- ob3分别给予链脲佐菌素（STZ）治疗的雄性瑞士韦氏小鼠和雄性饮食性肥胖（DIO）小鼠。脑切除，冠状切片用氟玉c （FJC）、硫黄素- s或苏木精和伊红（H&E）成像。ELISA法检测血清TNF-α、IGF-1水平。大脑皮质（CC）和海马（HC）的组织病理学改变与血糖调节、情景记忆和血清TNF-α和IGF-1水平的变化相关。结果胰岛素单独给药后小鼠血糖、血清TNF-α、IGF-1降低，MA-[D-Leu-4]- ob3与胰岛素联合给药后恢复正常。情节记忆的改善与CC和HC中fjc阳性细胞的数量以及血清TNF-α和IGF-1呈负相关。FJC、硫黄素- s和H&E染色未见Aβ沉积。在MA-[D-Leu-4]- ob3治疗的DIO小鼠中也观察到类似的结果。结论MA-[D-Leu-4]- ob3改善TIDM和T2DM小鼠情景记忆的机制可能与改善胰岛素敏感性和减轻TNF-α-诱导的神经退行性变有关。ema -[D-Leu-4]- ob3可能通过阻断这些疾病的胰岛素抵抗、神经炎症和神经退行性变的级联反应而应用于临床前和临床AD和AD样痴呆。
BackgroundExtracellular beta-amyloid (Aβ), intra-neuronal hyper-phosphorylated tau protein, and chronic inflammation are neuropathological hallmarks of Alzheimer's Disease (AD). A link between AD, insulin dysfunction, and tumor necrosis factor-alpha (TNF-α) in promoting both tau and Aβ pathologies in vivo has been proposed.MethodsMA-[D-Leu-4]-OB3 was given, with or without insulin, to streptozotocin (STZ)-treated male Swiss Webster mice, and to male diet-induced obese (DIO) mice. Brains were excised, and coronal sections were imaged with fluoro jade-C (FJC), thioflavin-S, or hematoxylin and eosin (H&E). Serum TNF-α and IGF-1 were measured by ELISA. Histopathological changes in the cerebral cortex (CC) and hippocampus (HC) were correlated with changes in glycemic regulation, episodic memory, and serum levels of TNF-α and IGF-1.ResultsIn STZ-treated mice, blood glucose and serum TNF-α and IGF-1 were reduced by insulin alone, and normalized when MA-[D-Leu-4]-OB3 was given in combination with insulin. Improvement in episodic memory was inversely correlated with the number of FJC-positive cells in the CC and HC and serum TNF-α and IGF-1. FJC, thioflavin-S and H&E staining indicated no Aβ deposition. Similar results were observed in DIO mice treated with MA-[D-Leu-4]-OB3.ConclusionsThe mechanism by which MA-[D-Leu-4]-OB3 improves episodic memory in mouse models of TIDM and T2DM appears to be related to improved insulin sensitivity and reduced TNF-α-induced neurodegeneration.General significanceMA-[D-Leu-4]-OB3 may have application to human pre-clinical and clinical AD and AD-like dementia by interrupting the cascade of insulin resistance, neuro-inflammation, and neurodegeneration, that characterizes these diseases.