β-Amyloid is transmitted via neuronal connections along axonal membranes
Ha-Lim Song MS
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSungbo Shim PhD
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorDong-Hou Kim MD, PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSe-Hoon Won PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSegyeong Joo PhD
Department of Biomedical Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSudong Kim PhD
Division of World Class University Multiscale Mechanical Design, School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Korea
Search for more papers by this authorNoo Li Jeon PhD
Division of World Class University Multiscale Mechanical Design, School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Korea
Search for more papers by this authorCorresponding Author
Seung-Yong Yoon MD, PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Address correspondence to Dr Yoon, Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul 138-736, Korea. E-mail: [email protected]Search for more papers by this authorHa-Lim Song MS
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSungbo Shim PhD
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorDong-Hou Kim MD, PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSe-Hoon Won PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSegyeong Joo PhD
Department of Biomedical Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Search for more papers by this authorSudong Kim PhD
Division of World Class University Multiscale Mechanical Design, School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Korea
Search for more papers by this authorNoo Li Jeon PhD
Division of World Class University Multiscale Mechanical Design, School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Korea
Search for more papers by this authorCorresponding Author
Seung-Yong Yoon MD, PhD
Alzheimer's Disease Experts Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
Address correspondence to Dr Yoon, Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, SongPa-Gu, Seoul 138-736, Korea. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
β-amyloid plaque is a critical pathological feature of Alzheimer disease. Pathologic studies suggest that neurodegeneration may occur in a retrograde fashion from axon terminals near β-amyloid plaques, and that plaque may spread through brain regions. However, there is no direct experimental evidence to show transmission of β-amyloid.
Methods
Microscopic imaging data of β-amyloid transmission was acquired in cortical neuron cultures from Sprague-Dawley rat embryos using polydimethylsiloxane (PDMS) microfluidic culture chambers and in brain sections from in vivo β-amyloid injection.
Results
We present direct imaging evidence in cultured cortical neurons, using PDMS microfluidic culture chambers, that β-amyloid is readily absorbed by axonal processes and retrogradely transported to neuronal cell bodies. Transmission of β-amyloid via neuronal connections was also confirmed in mouse brain. β-Amyloid absorbed by distal axons accumulates in axonal swellings, mitochondria, and lysosomes of the cell bodies. Interestingly, dynasore, an inhibitor of dynamin, which is a protein indispensable for endocytosis, did not prevent retrograde transport of β-amyloid, indicating that β-amyloid is absorbed onto axonal membranes and transmitted via them to the cell body. Dynasore did decrease the transneuronal transmission of β-amyloid, suggesting that this requires the internalization and secretion of β-amyloid.
Interpretation
Our findings provide direct in vitro and in vivo evidence for spreading of β-amyloid through neuronal connections, and suggest possible therapeutic approaches to blocking this spread. Ann Neurol 2014;75:88–97
Supporting Information
Additional supporting information can be found in the online version of this article.
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