Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
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DOI：
10.1084/jem.20132451
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发表时间：
2014-07-28
期刊：
影响因子：
--
通讯作者：
Bae JS
中科院分区：
文献类型：
--
作者：
Lee JK;Jin HK;Park MH;Kim BR;Lee PH;Nakauchi H;Carter JE;He X;Schuchman EH;Bae JS
小鼠和阿尔茨海默病患者的大脑和血浆中的酸性鞘磷脂酶活性增加，其抑制代表了这种疾病的潜在新治疗干预措施。在阿尔茨海默病（AD），异常鞘脂代谢已被报道，虽然这些变化的致病后果还没有得到充分的表征。我们发现，酸性鞘磷脂酶（ASM）增加成纤维细胞，脑，和/或血浆中的AD患者和AD小鼠，导致有缺陷的自噬降解由于溶酶体耗竭。在家族性AD小鼠模型（FAD;淀粉样前体蛋白[APP]/早老素1 [PS1]）中，部分遗传抑制ASM（ASM+/−）可通过恢复溶酶体生物发生来改善自噬缺陷，从而改善AD临床和病理学结果，包括减少淀粉样β（Aβ）沉积和改善记忆障碍。在APP/PS1小鼠中，将ASM药理学恢复至正常范围后，观察到类似效应。源自FAD患者诱导的多能干细胞（iPSC）的神经元中的自噬功能障碍通过部分ASM抑制而恢复。总体而言，这些结果揭示了AD中ASM发病机制的新机制，该机制由于溶酶体生物合成受损而导致有缺陷的自噬，并表明部分ASM抑制是该疾病的潜在新治疗干预。
Acid sphingomyelinase activity is increased in brain and plasma of mice and patients with Alzheimer’s disease and its inhibition represents a potential new therapeutic intervention for this disease. 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.
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影响因子：
5.3
作者：
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4.2
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通讯作者：
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影响因子：
82.9
作者：
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通讯作者：
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