Objectives: Triple-transgenic Alzheimer (3xTg-AD) mouse express mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develop plaques and neurofibrillary tangles with a temporaland region-specific profile that resembles the neuropathological progression of Alzheimer’s disease (AD). The main aim of this study was to evaluate changes in the protein changes underlying different stages of the disease progression in this AD model. Methods: In this study, we employed proteomic approaches, such as 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 female 3xTg-AD mice. Presenilin-1 knock-in (PS1KI) mice do not develop cognitive decline and were used as controls. Finally, employing the Ingenuity Pathway Analysis (IPA) we evaluated novel networks and molecular pathways involved in this AD model. Results: In 3xTg-AD brains, we identified several differentially expressed spots and their analysis showed a significant down-regulation of synaptic proteins associated with neurotransmitter synthesis, storage and release as well as a set of proteins that are associatedwith cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an up-regulation of proteins associated with carbohydrate metabolism and protein catabolism. Conclusion: Our proteomic study in the brain and cerebellum of 3xTg-AD mice show an interesting divergence of effects between these two CNS regions. In the brain, we observe a significant down-regulation of synaptic, cytoskeletal, and mitochondrial proteins, suggesting that synaptic and mitochondrial dysfunction are playing a key role in the later stage of the AD-like pathology observed in this region. In contrast, in the cerebellum we find an up-regulation of proteins that are involved in energy metabolism, clearance of misfolded protein, and detoxification. These findings are particularly intriguing as they may shed new light on endogenous mechanisms set in motion by the cerebellum to counteract the pathogenic actions of A-beta and p-tau and offer novel targets for therapeutic intervention.

Alterations of brain and cerebellum proteomes in 3xTg-AD mice

CIAVARDELLI, DOMENICO;
2010

Abstract

Objectives: Triple-transgenic Alzheimer (3xTg-AD) mouse express mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develop plaques and neurofibrillary tangles with a temporaland region-specific profile that resembles the neuropathological progression of Alzheimer’s disease (AD). The main aim of this study was to evaluate changes in the protein changes underlying different stages of the disease progression in this AD model. Methods: In this study, we employed proteomic approaches, such as 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 female 3xTg-AD mice. Presenilin-1 knock-in (PS1KI) mice do not develop cognitive decline and were used as controls. Finally, employing the Ingenuity Pathway Analysis (IPA) we evaluated novel networks and molecular pathways involved in this AD model. Results: In 3xTg-AD brains, we identified several differentially expressed spots and their analysis showed a significant down-regulation of synaptic proteins associated with neurotransmitter synthesis, storage and release as well as a set of proteins that are associatedwith cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an up-regulation of proteins associated with carbohydrate metabolism and protein catabolism. Conclusion: Our proteomic study in the brain and cerebellum of 3xTg-AD mice show an interesting divergence of effects between these two CNS regions. In the brain, we observe a significant down-regulation of synaptic, cytoskeletal, and mitochondrial proteins, suggesting that synaptic and mitochondrial dysfunction are playing a key role in the later stage of the AD-like pathology observed in this region. In contrast, in the cerebellum we find an up-regulation of proteins that are involved in energy metabolism, clearance of misfolded protein, and detoxification. These findings are particularly intriguing as they may shed new light on endogenous mechanisms set in motion by the cerebellum to counteract the pathogenic actions of A-beta and p-tau and 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/11387/41529
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