Department of Internal Medicine, The Catholic University of Korea College of Medicine, Uijeongbu St. Mary's Hospital, Uijeongbu, Korea.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Sci Rep. 2019 Mar 13;9(1):4414. doi: 10.1038/s41598-019-40736-x.
Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer's disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.
淀粉样蛋白-β（Aβ）在大脑中的积累是阿尔茨海默病（AD）的一种病理特征，增强 Aβ 的清除是一种潜在的治疗策略。吡格列酮是过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂，广泛用于治疗 2 型糖尿病。我们之前报道过，低剂量吡格列酮通过增加低密度脂蛋白受体相关蛋白 1（LRP1）的表达，上调 Aβ 的清除，从而增加人脑血管内皮细胞中 Aβ 的清除。我们通过增加 LRP1 水平，研究了低剂量吡格列酮是否可以通过增加 LRP1 水平来挽救衰老加速小鼠易感 8 型（SAMP8）小鼠的病理表型和记忆障碍。SAMP8 小鼠用载体或吡格列酮以 2 或 5mg/kg/天的剂量治疗 7 周。在水迷宫测试中，2mg/kg/天的吡格列酮显著降低了 SAMP8 小鼠的逃避潜伏期增加（p=0.026），而 5mg/kg/天的治疗没有。与载体处理相比，2mg/kg/天吡格列酮处理的 SAMP8 小鼠海马中 Aβ 沉积减少，Aβ 水平降低，LRP1 表达升高（p=0.005）。综上所述，我们的研究结果表明，PPAR-γ 激动剂的新治疗应用应考虑在治疗糖尿病的常规剂量以下的较低剂量。
