Aβ 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 A beta-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 A beta on gene regulation. We found that A beta and P301L tau expression independently affect the regulation of genes controlling cell proliferation and synaptic elements. Moreover, A beta 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 A beta treatment induces an early upregulation of cell cycle control and synaptic genes. At the protein level, by using Kinetworks (TM) multi-immunoblotting and BrdU labelling, we found that although P301L tau and A beta 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 A beta. Thus, our study shows that A beta 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.