Functional genomics dissects pathomechanisms in tauopathies:: Mitosis failure and unfolded protein response

Background. Alzheimer's disease (AD) is characterized by beta-amyloid (A beta) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of A beta(42), both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, A beta(42) induces tau aggregation. While both A beta(42) and mutant tau cause neuronal dysfunction, their modes of action are only vaguely understood. Methods: To determine which processes are disrupted by A beta(42) 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 AP(42) and P301L tau expression independently affect genes controlling the cell cycle and cell proliferation. Proteomics applied to A beta(42)-treated P301L tau-expressing SH-SY5Y cells and the amygdala of A beta(42)-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 re-entry of postmitotic neurons induces apoptosis. Furthermore, our data underline a role of AP(42) in the stress response associated with protein folding. Copyright (c) 2008 S. Karger AG, Basel.