| Amyloid beta: a putative intra-spinal microtubule-depolymerizer to induce synapse-loss or dentritic spine shortening in Alzheimer's disease. | |
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MedLine Citation:
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PMID: 20198823 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer's disease, but the underlying mechanisms are poorly understood. Recently, there have been four reports of capture of the plus-ends of microtubules in the dendritic spines. One report, based on acute hippocampal slices that were fixed by a microtubule preserving process after LTP-inducing stimulation, showed that microtubules of the dendritic shaft ramified into spines in a manner that was specific to the stimulated postsynaptic membranes. This resulted in enlarged protrusion of the dendritic spines. Other reports using living cultured neurons, showed that growing microtubule plus-ends enter spines and modulate spine morphology. Since microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. Several pieces of evidence suggest that spine elongation may be caused by microtubule polymerization. Firstly, the entry of plus-ends of microtubules into spines accompanies spine enlargement. Further, microtubule-associated protein-1B is over-expressed in Fragile X syndrome, in which spines are much elongated. Chronic stress causes neurite outgrowth and spine elongation. Polymerization of microtubules caused neurite outgrowth and microtubules-depolymerizing agents neurite retraction, both consistent with the proposition that spine elongation is caused by microtubule polymerization. This structural mechanism for spine elongation suggests, conversely, that synapse loss or spine shortening observed in Alzheimer's disease may be caused by depolymerization of intraspinal microtubules. The fact that a new drug, dimebon, shows promising results against memory disturbance in Alzheimer's patients and can also cause neurite outgrowth in cultured neurons may also support this idea. Amyloid activates GSK-3beta and it causes the abnormal hyperphosphorylation of tau and depolymerization of axonal microtubules, resulting in the impairment of axonal transport. Normal tau is mainly present in the axon, but hyperphosphorylated tau newly distributes to the dendrites and sequesters normal tau, MAP1A/MAP1B and MAP2, and may cause disruption of intraspinal microtubules by losing the microtubule-preserving effect of MAPs. Nevertheless, it may be strongly suspected that amyloid beta may be a putative intra-spinal microtubule-depolymerizer to induce spine shortening, synaptic loss and finally the memory disturbance in Alzheimer's disease. |
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Authors:
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Fuyuki Mitsuyama; Yoshio Futatsugi; Masato Okuya; Kostadin Karagiozov; Nikolay Peev; Yoko Kato; Tetsuo Kanno; Hirotoshi Sano; Tadashi Koide |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia Volume: 114 ISSN: 1122-6714 ISO Abbreviation: Ital J Anat Embryol Publication Date: 2009 Apr-Sep |
Date Detail:
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Created Date: 2010-03-04 Completed Date: 2010-06-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9612303 Medline TA: Ital J Anat Embryol Country: Italy |
Other Details:
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Languages: eng Pagination: 109-20 Citation Subset: IM |
Affiliation:
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Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan. fmituyam@hotmail.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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metabolism*,
pathology,
physiopathology Amyloid beta-Protein / metabolism* Animals Brain / metabolism*, pathology, physiopathology Dendritic Spines / metabolism*, pathology, ultrastructure Humans Microtubules / metabolism*, pathology, ultrastructure Nerve Degeneration / metabolism, pathology, physiopathology Polymers / metabolism Synapses / metabolism*, pathology Synaptic Transmission / physiology |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein; 0/Polymers |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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