Protein biochemistry of the human brain in neurodegeneration with emphasis on Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for up to fifty percent of all dementias, yet its pathogenic mechanisms remain poorly understood. In order to provide a more complete picture of pathogenesis in AD, six regions of the human brain were analysed for alterations in their proteomes; three of these areas are severely injured in the AD process, and three are relatively spared. By quantitative proteome analysis, signals corresponding to individual proteins from postmortem brain tissues from cases of AD were compared with those from non-degenerated control cases. Significant differences in protein levels between affected and control tissues were present in severely injured brain regions, but also in relatively spared regions. Variations in protein levels were not significantly associated with age, post-mortem delay, gender, case variability, or experimental artefacts. The molecular identity of forty-four significantly altered proteins was determined, twenty-five of which have previously been implicated in AD mechanisms. In addition, identified proteins represented key functional groupings, including synaptic neurotransmission, stress response, lipid homeostasis, glycolysis, and association with the pathogenesis of diabetes mellitus, all of which were previously implicated in AD pathogenesis. Quantitative proteome analysis was also used to compare individual proteins in six regions of the post-mortem human brain from a combination of AD and four other neurodegenerative diseases with non-degenerated control cases. Significant protein differences were present in all regions studied. The molecular identity of forty-three proteins was determined. These proteins also represent key functional pathways previously associated with AD and neurodegenerative disease, twenty-four of which have previously been directly implicated in neurodegenerative disease. Key pathways identified in this study support an emerging hypothesis that neurodegeneration is a complex process, involving both genetic and environmental risk factors. A common underlying disease process involving impaired cerebral metabolism and hypoperfusion may lead to a variety of clinical presentations, the most common of which is AD. These studies provide a unique molecular snapshot illustrating the complexity of interrelated disease mechanisms at work in complex, multifactorial diseases, and show that comparative proteome analysis is a method with the power to develop important new insights into pathogenic mechanisms in neurodegenerative disease.