Sohrabi Mona, Floden Angela M, Manocha Gunjan D, Klug Marilyn G, Combs Colin K
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States.
Department of Geriatrics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United States.
Front Cell Neurosci. 2020 Jul 3;14:200. doi: 10.3389/fncel.2020.00200. eCollection 2020.
Aging is a major risk factor for Alzheimer's disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9-10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.
衰老为阿尔茨海默病（AD）的主要风险因素。胰岛素样生长因子1受体（IGF-1R）调节整体衰老及寿命。然而，IGF-1对与年龄相关的AD病理及进展的作用极具争议。基于我们之前的研究工作，表达人类突变淀粉样前体蛋白（APP）和早老素1（PS-1）的AβPP/PS1双转基因小鼠与IGF-1缺陷的艾姆斯侏儒小鼠（df/df）杂交后，脑内IGF-1水平降低。随后，在此小鼠模型中观察到神经胶质增生、淀粉样β（Aβ）斑块沉积及Aβ浓度均有所降低。这支持了IGF-1可能促进疾病进展的假说。为评估IGF-1在AD中的作用，将9至10月龄的雄性同窝对照野生型及AβPP/PS1小鼠随机分为两个治疗组，分别给予对照载体（二甲基亚砜）和鬼臼苦素（PPP，一种选择性、竞争性且可逆的IGF-1R抑制剂）。这种可透过血脑屏障的抑制剂通过腹腔注射给药，剂量为1毫克/千克/天。每日注射7天后处死小鼠，收集脑、脾及肝脏以量化组织学及生化变化。经PPP处理的AβPP/PS1小鼠脑内不溶性Aβ减少。此外，药物处理后海马区小胶质细胞增生及蛋白p-酪氨酸水平降低。我们的数据表明，在该小鼠模型中IGF-1R信号传导与疾病进展相关。更重要的是，即使在中年阶段调节脑内IGF-1R信号通路也足以减轻疾病表型的某些方面。这表明针对IGF-1R通路的小分子疗法可能对晚期疾病治疗可行。
