title: Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease.
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.
authors: 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.
authors: Jong Kil
authors: JK
authors: Lee
authors: 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.
authors: Hee Kyung
authors: HK
authors: Jin
authors: 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.
authors: Min Hee
authors: MH
authors: Park
authors: 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.
authors: Bo-ra
authors: BR
authors: Kim
authors: Department of Neurology and Brain Research Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors: Phil Hyu
authors: PH
authors: Lee
authors: Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Hiromitsu
authors: H
authors: Nakauchi
authors: Mental Health Sciences Unit, Faculty of Brain Sciences, University College London, London WC1E 6DE, England, UK.
authors: Janet E
authors: JE
authors: Carter
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Xingxuan
authors: X
authors: He
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors: Edward H
authors: EH
authors: Schuchman
authors: 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 jsbae@knu.ac.kr.
authors: Jae-sung
authors: JS
authors: Bae
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D016229:Amyloid beta-Peptides; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008569:Memory Disorders / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; C580804:presenilin 1, mouse; D000469:Alkaline Phosphatase; D013108:Sphingomyelin Phosphodiesterase