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Vol. 7, No. 1-3, 2010
Issue release date: April 2010
Section title: Biology of Neurodegeneration
Free Access
Neurodegenerative Dis 2010;7:56–59
(DOI:10.1159/000283484)

Amyloid-β-Derived Diffusible Ligands Cause Impaired Axonal Transport of Mitochondria in Neurons

Wang X.a · Perry G.a, b · Smith M.A.a · Zhu X.a
aDepartment of Pathology, Case Western Reserve University, Cleveland, Ohio, and bCollege of Sciences, University of Texas at San Antonio, San Antonio, Tex., USA
email Corresponding Author

Abstract

Background: Alzheimer’s disease (AD) is the most prevalent form of dementia predominantly affecting the elderly. It is believed that soluble amyloid-β (Aβ) oligomers are involved in the pathogenesis of AD, yet the underlying mechanisms remain elusive. Objectives: Emerging evidence suggests that mitochondrial dysfunction likely plays a critical role in Aβ-induced neuronal degeneration. Previously, we demonstrated that Aβ-derived diffusible ligands (ADDLs) induce reduced mitochondrial density in neurites, and we suspect that an impaired mitochondrial trafficking might be involved, which is tested in this study. Methods: Using live cell imaging, anterograde and retrograde transport of mitochondria in primary hippocampal neurons treated with sub-lethal doses of ADDLs was measured. Results: We found that ADDLs induced significant impairment in both anterograde and retrograde transport of mitochondria along axons. Conclusion: These results suggest that an impaired mitochondrial transport likely contributes to ADDL-induced abnormal mitochondrial distribution and dysfunction and also reinforce the idea that axonal transport is likely involved in AD pathogenesis.

© 2010 S. Karger AG, Basel


  

Key Words

  • Aβ-derived diffusible ligands
  • Mitochondria
  • Axonal transport
  • Alzheimer’s disease

References

  1. Smith MA: Alzheimer disease. Int Rev Neurobiol 1998;42:1–54.
  2. Reddy PH: Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 2009;218:286–292.
  3. Wang X, Su B, Fujioka H, Zhu X: Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2008;173:470–482.
  4. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X: Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008;105:19318–19323.
  5. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X: Impaired mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009;29:9090–9103.
  6. Hollenbeck PJ, Saxton WM: The axonal transport of mitochondria. J Cell Sci 2005;118:5411–5419.
  7. Miller KE, Sheetz MP: Axonal mitochondrial transport and potential are correlated. J Cell Sci 2004;117:2791–2804.
  8. Rui Y, Tiwari P, Xie Z, Zheng JQ: Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 2006;26:10480–10487.
  9. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S: Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci USA 2009;106:5907–5912.
  10. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS: Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 2005;307:1282–1288.

  

Author Contacts

Xiongwei Zhu, PhD
Department of Pathology, Case Western Reserve University
2103 Cornell Road
Cleveland, OH 44106 (USA)
Tel. +1 216 368 5903, Fax +1 216 368 8964, E-Mail xiongwei.zhu@case.edu

  

Article Information

Published online: February 13, 2010
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 0, Number of References : 10

  

Publication Details

Neurodegenerative Diseases

Vol. 7, No. 1-3, Year 2010 (Cover Date: April 2010)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Alzheimer’s disease (AD) is the most prevalent form of dementia predominantly affecting the elderly. It is believed that soluble amyloid-β (Aβ) oligomers are involved in the pathogenesis of AD, yet the underlying mechanisms remain elusive. Objectives: Emerging evidence suggests that mitochondrial dysfunction likely plays a critical role in Aβ-induced neuronal degeneration. Previously, we demonstrated that Aβ-derived diffusible ligands (ADDLs) induce reduced mitochondrial density in neurites, and we suspect that an impaired mitochondrial trafficking might be involved, which is tested in this study. Methods: Using live cell imaging, anterograde and retrograde transport of mitochondria in primary hippocampal neurons treated with sub-lethal doses of ADDLs was measured. Results: We found that ADDLs induced significant impairment in both anterograde and retrograde transport of mitochondria along axons. Conclusion: These results suggest that an impaired mitochondrial transport likely contributes to ADDL-induced abnormal mitochondrial distribution and dysfunction and also reinforce the idea that axonal transport is likely involved in AD pathogenesis.

© 2010 S. Karger AG, Basel


  

Author Contacts

Xiongwei Zhu, PhD
Department of Pathology, Case Western Reserve University
2103 Cornell Road
Cleveland, OH 44106 (USA)
Tel. +1 216 368 5903, Fax +1 216 368 8964, E-Mail xiongwei.zhu@case.edu

  

Article Information

Published online: February 13, 2010
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 0, Number of References : 10

  

Publication Details

Neurodegenerative Diseases

Vol. 7, No. 1-3, Year 2010 (Cover Date: April 2010)

Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Article / Publication Details

First-Page Preview
Abstract of Biology of Neurodegeneration

Published online: 2/13/2010
Issue release date: April 2010

Number of Print Pages: 4
Number of Figures: 1
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Smith MA: Alzheimer disease. Int Rev Neurobiol 1998;42:1–54.
  2. Reddy PH: Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease. Exp Neurol 2009;218:286–292.
  3. Wang X, Su B, Fujioka H, Zhu X: Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2008;173:470–482.
  4. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X: Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008;105:19318–19323.
  5. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X: Impaired mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 2009;29:9090–9103.
  6. Hollenbeck PJ, Saxton WM: The axonal transport of mitochondria. J Cell Sci 2005;118:5411–5419.
  7. Miller KE, Sheetz MP: Axonal mitochondrial transport and potential are correlated. J Cell Sci 2004;117:2791–2804.
  8. Rui Y, Tiwari P, Xie Z, Zheng JQ: Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 2006;26:10480–10487.
  9. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S: Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci USA 2009;106:5907–5912.
  10. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS: Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 2005;307:1282–1288.