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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