Abeta treatment and P301L tau expression in an Alzheimer's disease tissue culture model act synergistically to promote aberrant cell cycle re-entry.
Microarrays enable the observation of gene expression in experimental models of Alzheimer's disease (AD), with implications for the human pathology. Histopathologically, AD is characterized by Abeta-containing plaques and tau-containing neurofibrillary tangles. Here, we used a human SH-SY5Y neuroblastoma cell system to assess the role of P301L mutant human tau expression, and treatment with or without Abeta on gene regulation. We found that Abeta and P301L tau expression independently affect the regulation of genes controlling cell proliferation and synaptic elements. Moreover, Abeta and P301L tau act synergistically on cell cycle and DNA damage genes, yet influence specific genes within these categories. By using neuronally differentiated P301L tau cells, we can show that Abeta treatment induces an early upregulation of cell cycle control and synaptic genes. At the protein level, by using Kinetworks multi-immunoblotting and BrdU labelling, we found that although P301L tau and Abeta both affected levels of cell cycle proteins, their effects were distinct, in particular concerning DNA damage proteins. Moreover, DNA synthesis was observed only when SH-SY5Y cells overexpressed human wild-type or P301L tau and were incubated with Abeta. Thus, our study shows that Abeta treatment and human tau overexpression in an AD cell culture model act synergistically to promote aberrant cell cycle re-entry, supporting the mitosis failure hypothesis in AD.
Hoerndli
Frederic J
FJ
Division of Psychiatry Research, University of Zurich, August Forel Str. 1, 8008 Zurich, Switzerland.
Pelech
Steven
S
Papassotiropoulos
Andreas
A
Götz
Jürgen
J
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000963:Antimetabolites; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D008959:Models, Neurological; D009447:Neuroblastoma / Q000378:metabolism; D046509:Tissue Culture Techniques; D016875:tau Proteins / Q000096:biosynthesis*
D016229:Amyloid beta-Peptides; D000963:Antimetabolites; D016875:tau Proteins; D001973:Bromodeoxyuridine