Beschreibung:
<jats:p><i>Background:</i> Alzheimer’s disease (AD) is characterized by β-amyloid (Aβ) peptide-containing plaques and tau-containing neurofibrillary tangles. By intracerebral injection of Aβ<sub>42</sub>, both pathologies have been combined in P301L tau mutant mice. Furthermore, in cell culture, Aβ<sub>42</sub> induces tau aggregation. While both Aβ<sub>42</sub> and mutant tau cause neuronal dysfunction, their modes of action are only vaguely understood. <i>Methods:</i> To determine which processes are disrupted by Aβ<sub>42</sub> and/or P301L mutant tau, we used transcriptomic and proteomic techniques followed by functional validation and analysis of human AD tissue.<i> Results:</i> Our transcriptomic study in the SH-SY5Y cell culture system revealed that Aβ<sub>42</sub> and P301L tau expression independently affect genes controlling the cell cycle and cell proliferation. Proteomics applied to Aβ<sub>42</sub>-treated P301L tau-expressing SH-SY5Y cells and the amygdala of Aβ<sub>42</sub>-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. <i>Conclusion:</i> 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 Aβ<sub>42</sub> in the stress response associated with protein folding.</jats:p>