Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures.

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.

journal_name

Curr Alzheimer Res

authors

Mota SI,Ferreira IL,Pereira C,Oliveira CR,Rego AC

doi

10.2174/156720512802455322

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

844-56

issue

7

eissn

1567-2050

issn

1875-5828

pii

CAR-EPUB-20120521-20

journal_volume

9

pub_type

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