Increased membrane cholesterol might render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity.
A growing body of evidence suggests that beta-amyloid (Abeta), 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, Abeta 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 Abeta-dependent 17 kDa tau production at different developmental stages. Our results revealed that mature neurons were more susceptible to Abeta-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 Abeta-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 Abeta-dependent calpain activation, 17 kDa tau production, and cell death, whereas increasing membrane cholesterol in young neurons enhanced these Abeta-mediated cellular processes. Finally, fura-2 calcium imaging indicated that membrane cholesterol alterations might change the vulnerability of cells to Abeta insult by altering calcium influx. Together these data suggested a potential role of cholesterol in linking aging to Abeta-induced tau proteolysis in the context of AD.
Nicholson
Alexandra M
AM
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Ferreira
Adriana
A
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008563:Membrane Lipids / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids; D010446:Peptide Fragments; D016875:tau Proteins; D002784:Cholesterol; D002154:Calpain