Triple-transgenic Alzheimer (3xTg-AD) mice express mutant PS1M146V, APPswe, and tauP301L transgenes and develop amyloid and tau pathology with a temporal- and region-specific profile that resembles the pathological progression of Alzheimer’s disease (AD). In this study, we employed two-dimensional gel electrophoresis (2D-E) and mass spectrometry (MS) to investigate the alterations in protein expression occurring in the brain and cerebellum of 14-month old 3xTg-AD mice. Presenilin-1 knock-in (PS1KI) mice that do not develop cognitive decline were used as control. Employing the Ingenuity Pathway Analysis (IPA) we also evaluated novel networks and molecular pathways involved in this AD model. The results of our study indicate that 3xTg-AD brains showed a significant down-regulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release as well as proteins associated with cytoskeleton assembly and energy metabolism. Interestingly, the cerebellum, a structure not affected by AD, showed an up-regulation of proteins related to carbohydrate metabolism and protein catabolism. In summary, our proteomic study in the brain and cerebellum of 3xTg-AD mice shows an interesting divergence of effects between these two CNS regions. In the brain, our findings suggest that synaptic and mitochondrial dysfunction are playing a key role in the later stage of the AD-like pathology of this region. In contrast, the cerebellum shows an up-regulation of proteins involved in energy metabolism, clearance of misfolded proteins, and detoxification. These results reveal endogenous mechanisms set in motion by the cerebellum to counteract the pathogenic actions of Aβ and p-tau and ultimately offer novel targets for therapeutic intervention.

Protein expression profile in the brain and cerebellum of female 3xTg-AD mice

CIAVARDELLI, DOMENICO;
2010

Abstract

Triple-transgenic Alzheimer (3xTg-AD) mice express mutant PS1M146V, APPswe, and tauP301L transgenes and develop amyloid and tau pathology with a temporal- and region-specific profile that resembles the pathological progression of Alzheimer’s disease (AD). In this study, we employed two-dimensional gel electrophoresis (2D-E) and mass spectrometry (MS) to investigate the alterations in protein expression occurring in the brain and cerebellum of 14-month old 3xTg-AD mice. Presenilin-1 knock-in (PS1KI) mice that do not develop cognitive decline were used as control. Employing the Ingenuity Pathway Analysis (IPA) we also evaluated novel networks and molecular pathways involved in this AD model. The results of our study indicate that 3xTg-AD brains showed a significant down-regulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release as well as proteins associated with cytoskeleton assembly and energy metabolism. Interestingly, the cerebellum, a structure not affected by AD, showed an up-regulation of proteins related to carbohydrate metabolism and protein catabolism. In summary, our proteomic study in the brain and cerebellum of 3xTg-AD mice shows an interesting divergence of effects between these two CNS regions. In the brain, our findings suggest that synaptic and mitochondrial dysfunction are playing a key role in the later stage of the AD-like pathology of this region. In contrast, the cerebellum shows an up-regulation of proteins involved in energy metabolism, clearance of misfolded proteins, and detoxification. These results reveal endogenous mechanisms set in motion by the cerebellum to counteract the pathogenic actions of Aβ and p-tau and ultimately offer novel targets for therapeutic intervention.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11387/101130
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