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IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer's Disease Transgenic Mouse Model.
Frontiers in Cellular Neuroscience ( IF 4.2 ) Pub Date : 2020-06-08 , DOI: 10.3389/fncel.2020.00200
Mona Sohrabi 1 , Angela M Floden 1 , Gunjan D Manocha 2 , Marilyn G Klug 3 , Colin K Combs 1
Affiliation  

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 Aβ1–40/42 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 Aβ1–40/42. 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.



中文翻译:

IGF-1R抑制剂可改善阿尔茨海默氏病转基因小鼠模型中的神经炎症。

衰老是阿尔茨海默氏病(AD)的主要危险因素。胰岛素样生长因子1受体(IGF-1R)调节总体衰老和寿命。但是,IGF-1在与年龄有关的AD病理和进展中的作用引起很大争议。根据我们之前的工作,表达人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杂交时,大脑IGF-1水平降低。矮小的Ames矮小鼠(df / df)。随后,胶质增生,淀粉样β(Aβ)斑块沉积和Aβ1–40 / 42减少在该小鼠模型中观察到浓度。这支持了IGF-1可能有助于疾病进展的假说。为评估IGF-1在AD中的作用,将9-10个月大的雄性同窝对照野生型和AβPP/ PS1小鼠随机分为两个治疗组,包括对照媒介物(DMSO)和鬼臼苦素(PPP),竞争性和可逆性IGF-1R抑制剂。ip给予脑渗透抑制剂。1 mg / kg /天。每天注射7天后处死小鼠,收集大脑,脾脏和肝脏以量化组织学和生化变化。PPP治疗的AβPP/ PS1小鼠表现出减毒的不溶性Aβ1–40 / 42。另外,由于海马中的药物治疗,观察到小胶质细胞增生和蛋白对酪氨酸水平降低。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,大脑IGF-1R信号通路的调节也足以减弱疾病表型的某些方面。这表明靶向IGF-1R途径的小分子疗法对于晚期疾病治疗可能是可行的。

更新日期:2020-07-03
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