Abstract
BackgroundAtypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD.ResultsOur studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition.ConclusionsThe data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis.
Highlights
Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer’s disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood
Mice expressing amyloid precursor protein (APP) alone showed a smaller increase in the level of these cell cycle regulatory proteins compared to the double transgenic mice (Figure 1A, d compared to 1A, e), possibly due to the differences in the transgene expression and the fact that PS/APP mice develop pathology at an earlier age compared to APP expressing mice
In conclusion, cell cycle deregulation may influence the pathogenesis of AD through multiple pathways: 1) through phosphorylation and processing of APP to generate Ab leading to plaque formation, 2) through Ab and C-terminal fragment of APP inducing tau hyperphosphorylation [66,74,75,76], and 3) through both Ab and P-APP affecting cell cycle deregulation and contributing to the unwarranted progression of cell cycle
Summary
Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer’s disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. In addition to neuronal loss, it is possible that dysregulation of the cell cycle may lead to cell cycle-dependent modifications in the amyloid precursor protein (APP) and tau, the two major proteins associated with AD, favouring plaque and tangle formation and neurodegeneration in the AD brains. In addition to the accumulation of Ab into amyloid, studies in neurons have shown that Ab peptides can induce cell cycle activation and neuronal apoptosis [35]. Mice generally do not show much neuronal loss, but it is possible that the upregulation of cell cycle regulatory proteins may mediate synaptic loss and neurodegeneration by inducing modifications in tau and APP. We analyzed the specific effects of cell cycle activation on APP modifications
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