Abstract
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder among the elderly. Nmethyl- D-aspartate receptor (NMDAR) overactivation has been implicated in early synaptic dysfunction that precedes late neurodegeneration in AD. Moreover, oligomers of amyloid-beta peptide (Aβ) 1-42 are considered the most synaptotoxic forms, responsible for early cognitive deficits in AD. In this work we evaluate the role of NMDARs on Aβ-evoked neuronal dysfunction and cell death through changes in microtubule polymerization in mature hippocampal cultures. Exposure to Aβ 1-42 caused a decrease in total and polymerized levels of beta-III tubulin and polymerized alpha-tubulin, suggesting microtubule disassembly. Moreover, Aβ induced DNA fragmentation in both neuronal and non-neuronal cells. Indeed, the effects of Aβ on beta-III tubulin polymerization were significantly correlated with reduced neurite length and neuronal DNA fragmentation. Interestingly, these effects were prevented by MK-801 and memantine, suggesting a role for extrasynaptic NMDARs in Aβ toxicity, and by ifenprodil, further indicating the involvement of GluN2B-containing NMDARs. Nevertheless, exposure to Aβ did not potentiate the effects caused by selective activation of NMDARs. Data largely suggest that Aβ-induced hippocampal neuronal dysfunction occurs through NMDAR-dependent microtubule disassembly associated to neurite retraction and DNA fragmentation in mature hippocampal cells.
Keywords: Alzheimer’s disease, amyloid-beta peptide, DNA fragmentation, hippocampal cells, microtubules, NMDA receptors, GluN2B subunit, fluorescence microscopy.
Current Alzheimer Research
Title:Amyloid-Beta Peptide 1-42 Causes Microtubule Deregulation through N-methyl-D-aspartate Receptors in Mature Hippocampal Cultures
Volume: 9 Issue: 7
Author(s): Sandra I. Mota, Ildete L. Ferreira, Claudia Pereira, Catarina R. Oliveira and A. Cristina Rego
Affiliation:
Keywords: Alzheimer’s disease, amyloid-beta peptide, DNA fragmentation, hippocampal cells, microtubules, NMDA receptors, GluN2B subunit, fluorescence microscopy.
Abstract: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder among the elderly. Nmethyl- D-aspartate receptor (NMDAR) overactivation has been implicated in early synaptic dysfunction that precedes late neurodegeneration in AD. Moreover, oligomers of amyloid-beta peptide (Aβ) 1-42 are considered the most synaptotoxic forms, responsible for early cognitive deficits in AD. In this work we evaluate the role of NMDARs on Aβ-evoked neuronal dysfunction and cell death through changes in microtubule polymerization in mature hippocampal cultures. Exposure to Aβ 1-42 caused a decrease in total and polymerized levels of beta-III tubulin and polymerized alpha-tubulin, suggesting microtubule disassembly. Moreover, Aβ induced DNA fragmentation in both neuronal and non-neuronal cells. Indeed, the effects of Aβ on beta-III tubulin polymerization were significantly correlated with reduced neurite length and neuronal DNA fragmentation. Interestingly, these effects were prevented by MK-801 and memantine, suggesting a role for extrasynaptic NMDARs in Aβ toxicity, and by ifenprodil, further indicating the involvement of GluN2B-containing NMDARs. Nevertheless, exposure to Aβ did not potentiate the effects caused by selective activation of NMDARs. Data largely suggest that Aβ-induced hippocampal neuronal dysfunction occurs through NMDAR-dependent microtubule disassembly associated to neurite retraction and DNA fragmentation in mature hippocampal cells.
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Cite this article as:
I. Mota Sandra, L. Ferreira Ildete, Pereira Claudia, R. Oliveira Catarina and Cristina Rego A., Amyloid-Beta Peptide 1-42 Causes Microtubule Deregulation through N-methyl-D-aspartate Receptors in Mature Hippocampal Cultures, Current Alzheimer Research 2012; 9 (7) . https://dx.doi.org/10.2174/156720512802455322
DOI https://dx.doi.org/10.2174/156720512802455322 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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