作者
Jong Kil Lee, Hee Kyung Jin, Min Hee Park, Bo-ra Kim, Phil Hyu Lee, Hiromitsu Nakauchi, Janet E Carter, Xingxuan He, Edward H Schuchman, Jae-sung Bae
发表日期
2014/7/28
期刊
Journal of Experimental Medicine
卷号
211
期号
8
页码范围
1551-1570
出版商
The Rockefeller University Press
简介
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 …
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JK Lee, HK Jin, MH Park, B Kim, PH Lee, H Nakauchi… - Journal of Experimental Medicine, 2014