Increased membrane cholesterol might render mature hippocampal neurons more susceptible to β-Amyloid-induced calpain activation and tau toxicity

Alexandra M. Nicholson, Adriana Ferreira*

*Corresponding author for this work

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

A growing body of evidence suggests that β-amyloid (Aβ), the main component of senile plaques, induces abnormal posttranslational processing of the microtubule-associated protein tau. We have recently described that, in addition to increasing tau phosphorylation, Aβ enhanced calpain activity leading to the generation of a toxic 17 kDa tau fragment in cultured hippocampal neurons. How aging, the greatest Alzheimer's disease (AD) risk factor, might regulate this proteolytic event remains unknown. In this study, we assessed the susceptibility of cultured hippocampal neurons to Aβ-dependent 17 kDa tau production at different developmental stages. Our results revealed that mature neurons were more susceptible to Aβ-induced calpain activation leading to the generation of this fragment than young neurons. In addition, the production of this fragment correlated with a decrease in cell viability in mature hippocampal neurons. Second, we determined whether membrane cholesterol, a suspect player in AD, might mediate these age-dependent differences in Aβ-induced calpain activation. Filipin staining and an Amplex Red cholesterol assay showed that mature neuron membrane cholesterol levels were significantly higher than those detected in young ones. Furthermore, decreasing membrane cholesterol in mature neurons reduced their susceptibility to Aβ-dependent calpain activation, 17 kDa tau production, and cell death, whereas increasing membrane cholesterol in young neurons enhanced these Aβ-mediated cellular processes. Finally, fura-2 calcium imaging indicated that membrane cholesterol alterations might change the vulnerability of cells to Aβ insult by altering calcium influx. Together these data suggested a potential role of cholesterol in linking aging to Aβ-induced tau proteolysis in the context of AD.

Original languageEnglish (US)
Pages (from-to)4640-4651
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number14
DOIs
StatePublished - Apr 8 2009

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ASJC Scopus subject areas

  • Neuroscience(all)

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