Alzheimer Disease Pathological Processes Investigation By Systems Biology Approach

Alzheimer's disease (AD) affects millions of people in the world, prevalently elder ones, but so far treatments that prevent, block or effectively slow down the disease are scarce. Important efforts have been devoted to the research of effective drugs, leading to a huge amount of data from numerous high-throughput studies and existing in vitro and animal models, but clinical trials did not fulfilled expectations. Like other neurodegenerative diseases, AD is related to protein misfolding in the brain: the pathology involves a complex cascade that the main hypotheses lead back to the accumulation of beta-amyloid (Abeta) peptide aggregates. AD is also related to abnormal aggregation of the tau protein (tau), a protein involved in microtubules stabilization, which in the pathology undergoes hyper-phosphorylation, forming neurofibrillary tangles that interfere with the normal neuron's intracellular transport processes.
Multiple pathways are perturbed during the pathology leading to inflammation, oxidative damage, tau pathology and the loss of neurons and synapses. Furthermore the differences existing between AD animal models and human pathology renders difficult to effectively use the experimental evidences. Systems biology represents a promising approach to overcome the aforementioned limitations and can be used to study brain ageing at multiple levels integrating quantitative systems analysis, genomics, proteomics and pathophysiology.
In this project, we will reconstruct proteins interactions networks involving Abeta using verified and predictive interatomic. We will analyse the pathways topology, selecting those enriched in Gene Ontology classes significant for AD biological processes and cellular localization. Pathways selection will furthermore take into account the genetic expression profiles after Abeta administration, in particular those coherent with experimental result.
High throughput investigations are particularly valuable when dealing with complex systems where several proteins interact in the regulation of biological processes. Several microarrays data are available at Arrayexpress or GEO databanks, where tissues from humans or mice AD models were analysed to study the effect of Abeta compared to the normal condition.
Results obtained will be object of further verification in our group using relevant animals models of human neurological diseases, proteomic techniques and microscopy (multi-photon and confocal) and several electrophysiological techniques.

Contacts

For more information about this project, please, contact Prof. Mario Buffelli and Dr. Simone Zorzan