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J. Exp. Med., Published July 21, 2014 | doi: 10.1084/jem.20132451 Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer’s disease

Abstract

Jong Kil Lee,^1,2,3,† Hee Kyung Jin,^1,4,† Min Hee Park,^1,2,3 Bo-ra Kim,^1,2,3 Phil Hyu Lee,⁵ Hiromitsu Nakauchi,⁶ Janet E. Carter,⁷ Xingxuan He,⁸ Edward H. Schuchman,⁸ and Jae-sung Bae^1,2,3,*

¹Stem Cell Neuroplasticity Research Group, ²Department of Physiology, Cell and Matrix Research Institute, School of Medicine, ³Department of Biomedical Science, BK21 Plus KNU Biomedical Convergence Program, ⁴Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Korea
⁵Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea ⁶Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
⁷Mental Health Sciences Unit, Faculty of Brain Sciences, University College London, London WC1E 6DE, England, UK
⁸Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029

^†J.K. Lee and H.K. Jin contributed equally to this paper.
^*CORRESPONDENCE : Jae-sung Bae

Abstract
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.

논문정보

형식Research article
게재일2014년 07월 (BRIC 등록일 2014-07-28)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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