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Regional Variation and Novel Pathogenesis in the Human Alzheimer’s Disease Brain
EP27363
Poster Title: Regional Variation and Novel Pathogenesis in the Human Alzheimer’s Disease Brain
Submitted on 20 Mar 2018
Author(s): Jingshu Xu, Nitin Rustogi, Benjamin A Hale, Adam Stevens, Richard Faull, Andrew W Dowsey, Garth JS Cooper, and Richard D Unwin
Affiliations: The University of Manchester
This poster was presented at Alzheimer's Research UK Conference 2018
Poster Views: 989
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Poster Information
Abstract: Background. Alzheimer’s disease (AD) is a leading cause of death in the developed world. Despite increased focus, there are no effective therapies; even the root causes of AD remain controversial. While amyloid plaques and tau tangles are thought key to pathogenesis, targeting these pathways has yielded little success. New targets, and new insights into disease development, are urgently required. We have analysed protein expression across six distinct regions of human AD-affected brains versus age-matched controls to reveal novel cellular mechanisms associated with disease.

Methods. Matched brain tissue (n=9 per class) was acquired from the Auckland brain bank and six regions covering affected and ‘spared’ regions, namely hippocampus (HP), entorhinal cortex (ENT), cingulate gyrus (CG), sensory cortex (SCx), motor cortex (MCx), and cerebellum (CB) were dissected. Relative protein expression was determined by iTRAQ LC-MS/MS analysis followed by Bayesian statistics to determine differences between cases and controls. Pathway analysis (Ingenuity) and correlation network analysis (Moduland/Cytoscape) were subsequently performed to compare both disease vs. control and distinct brain regions.

Results. Over 5000 proteins were quantified in total, with 1,903 quantified by ≥3 peptides in all six regions. Pathway analysis revealed neuroinflammation across the brain, albeit more marked in affected regions. Additional metabolic and signalling pathways were observed in more affected regions, in agreement with previous studies and suggestive of an ‘evolution’ through the organ. Strikingly, cerebellum, a region thought to be spared, exhibited a significant number of alterations in its proteome which were unique, and which could be protective against neurodegeneration in this region.

Conclusions. We have developed an in-depth picture of protein expression in late-stage AD, with some regions displaying what we believe to be an ‘early-AD’ phenotype, and an active protective phenotype in cerebellum. This provides critical new data on AD pathogenesis, and reveals new pathways for potential therapeutic targeting.
Summary: We have determined protein expression changes in response to Alzheimer's disease in six distinct regions of the human brain. This enables us to identify novel features of pathogenesis, and to determine how distinct brain regions respond to disease and identify 'early' disease changes in less affected regions. In addition, we have identified the 'spared' cerebellum, initiates a programme of protein expression changes which is expected to actively protect this region from AD-related damage.References: Report abuse »
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