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_1–40/42 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 Aβ_1–40/42. 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.

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。