Background: Alzheimer’s disease (AD) is characterized by β-amyloid (Aβ) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of Aβ42, both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, Aβ42 induces tau aggregation. While both Aβ42 and mutant tau cause neuronal dysfunction, their modes of action are only vaguely understood. Methods: To determine which processes are disrupted by Aβ42 and/or P301L mutant tau, we used transcriptomic and proteomic techniques followed by functional validation and analysis of human AD tissue. Results: Our transcriptomic study in the SH-SY5Y cell culture system revealed that Aβ42 and P301L tau expression independently affect genes controlling the cell cycle and cell proliferation. Proteomics applied to Aβ42-treated P301L tau-expressing SH-SY5Y cells and the amygdala of Aβ42-injected P301L transgenic mice revealed that a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. Among the proteins identified was valosin-containing protein (VCP), a component of the quality control system during endoplasmic reticulum stress. Mutations in VCP have recently been linked to frontotemporal dementia. Conclusion: Our data support the mitosis failure hypothesis that claims that aberrant cell cycle reentry of postmitotic neurons induces apoptosis. Furthermore, our data underline a role of Aβ42 in the stress response associated with protein folding.

Keywords:
Alzheimer’s disease, β-Amyloid, Frontotemporal dementia, Proteomics, P301L tau, Transcriptomics, Transgenic mice, Valosin-containing protein
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© 2008 S. Karger AG, Basel
2008
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