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Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons
Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca(2+)-...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357506/ https://www.ncbi.nlm.nih.gov/pubmed/25609087 http://dx.doi.org/10.1091/mbc.E14-12-1612 |
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author | Gan, Kathlyn J. Silverman, Michael A. |
author_facet | Gan, Kathlyn J. Silverman, Michael A. |
author_sort | Gan, Kathlyn J. |
collection | PubMed |
description | Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca(2+) elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca(2+) influx through axonal voltage-gated Ca(2+) channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca(2+) release from the ER. This work establishes a novel role for Ca(2+) dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD. |
format | Online Article Text |
id | pubmed-4357506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-43575062015-05-30 Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons Gan, Kathlyn J. Silverman, Michael A. Mol Biol Cell Articles Disruption of fast axonal transport (FAT) and intracellular Ca(2+) dysregulation are early pathological events in Alzheimer's disease (AD). Amyloid-β oligomers (AβOs), a causative agent of AD, impair transport of BDNF independent of tau by nonexcitotoxic activation of calcineurin (CaN). Ca(2+)-dependent mechanisms that regulate the onset, severity, and spatiotemporal progression of BDNF transport defects from dendritic and axonal AβO binding sites are unknown. Here we show that BDNF transport defects in dendrites and axons are induced simultaneously but exhibit different rates of decline. The spatiotemporal progression of FAT impairment correlates with Ca(2+) elevation and CaN activation first in dendrites and subsequently in axons. Although many axonal pathologies have been described in AD, studies have primarily focused only on the dendritic effects of AβOs despite compelling reports of presynaptic AβOs in AD models and patients. Indeed, we observe that dendritic CaN activation converges on Ca(2+) influx through axonal voltage-gated Ca(2+) channels to impair FAT. Finally, FAT defects are prevented by dantrolene, a clinical compound that reduces Ca(2+) release from the ER. This work establishes a novel role for Ca(2+) dysregulation in BDNF transport disruption and tau-independent Aβ toxicity in early AD. The American Society for Cell Biology 2015-03-15 /pmc/articles/PMC4357506/ /pubmed/25609087 http://dx.doi.org/10.1091/mbc.E14-12-1612 Text en © 2015 Gan and Silverman. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Gan, Kathlyn J. Silverman, Michael A. Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title | Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title_full | Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title_fullStr | Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title_full_unstemmed | Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title_short | Dendritic and axonal mechanisms of Ca(2+) elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons |
title_sort | dendritic and axonal mechanisms of ca(2+) elevation impair bdnf transport in aβ oligomer–treated hippocampal neurons |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357506/ https://www.ncbi.nlm.nih.gov/pubmed/25609087 http://dx.doi.org/10.1091/mbc.E14-12-1612 |
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