Amyloid-Beta Peptide 1-42 Causes Microtubule Deregulation through N-methyl-D-aspartate Receptors in Mature Hippocampal Cultures

Author(s): Sandra I. Mota, Ildete L. Ferreira, Claudia Pereira, Catarina R. Oliveira, A. Cristina Rego.

Journal Name: Current Alzheimer Research

Volume 9 , Issue 7 , 2012

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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.

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Article Details

VOLUME: 9
ISSUE: 7
Year: 2012
Page: [844 - 856]
Pages: 13
DOI: 10.2174/156720512802455322
Price: $58

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