酸性鞘磷脂酶通过控制阿尔茨海默病中的溶酶体生物发生来调节自噬过程。
Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
机构信息
Stem Cell Neuroplasticity Research Group, Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, KoreaStem Cell Neuroplasticity Research Group, Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, KoreaStem Cell Neuroplasticity Research Group, Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.
Stem Cell Neuroplasticity Research Group, Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, KoreaStem Cell Neuroplasticity Research Group, Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea.
出版信息
J Exp Med. 2014 Jul 28;211(8):1551-70. doi: 10.1084/jem.20132451. Epub 2014 Jul 21.
In Alzheimer's disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (ASM(+/-)) in a mouse model of familial AD (FAD; amyloid precursor protein [APP]/presenilin 1 [PS1]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease.
在阿尔茨海默病（AD）中，已经报道了异常的鞘脂代谢，尽管这些变化的致病后果尚未完全阐明。我们表明，酸性鞘磷脂酶（ASM）在 AD 患者的成纤维细胞、大脑和/或血浆中以及 AD 小鼠中增加，导致溶酶体耗竭导致自噬降解缺陷。在家族性 AD（FAD；淀粉样前体蛋白 [APP]/早老素 1 [PS1]）的小鼠模型中，ASM 的部分遗传抑制（ASM(+/-)）通过恢复溶酶体生物发生来改善自噬缺陷，从而改善 AD 的临床和病理发现，包括减少淀粉样蛋白-β（Aβ）沉积和改善记忆障碍。在 APP/PS1 小鼠中，将 ASM 恢复到正常范围的药物治疗也观察到类似的效果。源自 FAD 患者诱导多能干细胞（iPSC）的神经元中的自噬功能障碍通过部分 ASM 抑制得到恢复。总体而言，这些结果揭示了 AD 中 ASM 发病机制的新机制，该机制导致溶酶体生物发生受损导致自噬缺陷，并表明部分 ASM 抑制是该疾病的一种潜在新的治疗干预措施。
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