Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612 and.
Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
J Neurosci. 2018 Jul 25;38(30):6682-6699. doi: 10.1523/JNEUROSCI.0054-18.2018. Epub 2018 Jul 2.
Lysosomes play a central role in cellular homeostasis by regulating the cellular degradative machinery. Because aberrant lysosomal function has been associated with multiple lysosomal storage and neurodegenerative disorders, enhancement of lysosomal clearance has emerged as an attractive therapeutic strategy. Transcription factor EB (TFEB) is known as a master regulator of lysosomal biogenesis and, here, we reveal that aspirin, one of the most widely used medications in the world, upregulates TFEB and increases lysosomal biogenesis in brain cells. Interestingly, aspirin induced the activation of peroxisome proliferator-activated receptor alpha (PPARα) and stimulated the transcription of via PPARα. Finally, oral administration of low-dose aspirin decreased amyloid plaque pathology in both male and female 5X familial Alzheimer's disease (5XFAD) mice in a PPARα-dependent fashion. This study reveals a new function of aspirin in stimulating lysosomal biogenesis via PPARα and suggests that low-dose aspirin may be used in lowering storage materials in Alzheimer's disease and lysosomal storage disorders. Developing drugs for the reduction of amyloid β containing senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD), is an important area of research. Aspirin, one of the most widely used medications in the world, activates peroxisome proliferator-activated receptor alpha (PPARα) to upregulate transcription factor EB and increase lysosomal biogenesis in brain cells. Accordingly, low-dose aspirin decreases cerebral plaque load in a mouse model of Alzheimer's disease via PPARα. These results reveal a new mode of action of aspirin that may be beneficial for AD and lysosomal storage disorders.
溶酶体通过调节细胞降解机制在细胞内稳态中发挥核心作用。由于异常的溶酶体功能与多种溶酶体贮积症和神经退行性疾病有关，因此增强溶酶体清除已成为一种有吸引力的治疗策略。转录因子 EB（TFEB）是溶酶体生物发生的主要调节因子，在这里，我们揭示了世界上使用最广泛的药物之一阿司匹林上调 TFEB 并增加脑细胞中的溶酶体生物发生。有趣的是，阿司匹林诱导过氧化物酶体增殖物激活受体α（PPARα）的激活，并通过 PPARα 刺激 的转录。最后，低剂量阿司匹林口服给药以 PPARα 依赖性方式降低了雄性和雌性 5X 家族性阿尔茨海默病（5XFAD）小鼠中的淀粉样斑块病理学。这项研究揭示了阿司匹林通过 PPARα 刺激溶酶体生物发生的新功能，并表明低剂量阿司匹林可用于降低阿尔茨海默病和溶酶体贮积症中的贮存物质。开发用于减少淀粉样β（淀粉样β）的药物，淀粉样β是阿尔茨海默病（AD）的病理标志之一，是一个重要的研究领域。阿司匹林是世界上使用最广泛的药物之一，它通过激活过氧化物酶体增殖物激活受体α（PPARα）来上调转录因子 EB 并增加脑细胞中的溶酶体生物发生。因此，低剂量阿司匹林通过 PPARα 降低了阿尔茨海默病小鼠模型中的脑斑块负荷。这些结果揭示了阿司匹林的一种新作用模式，可能对 AD 和溶酶体贮积症有益。
