Abstract
We applied a self-guiding evolutionary algorithm to initiate the synthesis of the Alzheimer's disease-related data and literature. A protein interaction network associated with amyloid-beta precursor protein (APP) and a seed model that treats Alzheimer's disease as progressive dysregulation of APP-associated signaling were used as dynamic "guides" and structural "filters" in the recursive search, analysis, and assimilation of data to drive the evolution of the seed model in size, detail, and complexity. Analysis of data and literature across sub-disciplines and system-scale discovery platforms suggests a key role of dynamic cytoskeletal connectivity in the stability, plasticity, and performance of multicellular networks and architectures. Chronic impairment and/or dysregulation of cell adhesions/synapses, cytoskeletal networks, and/or reversible epithelial-to-mesenchymal-like transitions, which enable and mediate the stable and coherent yet dynamic and reconfigurable multicellular architectures, may lead to the emergence and persistence of the disordered, wound-like pockets/microenvironments of chronically disconnected cells. Such wound-like microenvironments support and are supported by pro-inflammatory, pro-secretion, de-differentiated cellular phenotypes with altered metabolism and signaling. The co-evolution of wound-like microenvironments and their inhabitants may lead to the selection and stabilization of degenerated cellular phenotypes, via acquisition of epigenetic modifications and mutations, which eventually result in degenerative disorders such as cancer and Alzheimer's disease.
Highlights
Due to the introduction and success of highthroughput discovery platforms and the ever-increasing productivity of experimental research, the rate of data generation noticeably exceeds the rate at which data are translated into answers, solutions, products, and therapies
It is possible that many answers and solutions are already present in research literature and databases but in a disarranged and dispersed form, similar to the images hidden in the pieces of jigsaw puzzles that accumulate in a growing number of separate boxes, in which they are neatly sorted on the basis of their size, color, shape, or weight
Simplifying, one can discriminate between two mechanisms by which cells satisfy their energy needs – oxidative phosphorylation and “(glyco)lytic” modes of metabolism
Summary
Due to the introduction and success of highthroughput discovery platforms and the ever-increasing productivity of experimental research, the rate of data generation noticeably exceeds the rate at which data are translated into answers, solutions, products, and therapies. The model is given a large experimental dataset generated by system-scale www.impactjournals.com/oncotarget technologies, which is deemed to be of utmost importance, according to the model In this particular case, it is a protein interaction network centered on amyloid-beta precursor protein (APP), by common consensus one of the key players in the pathogenesis of Alzheimer’s disease. It is a protein interaction network centered on amyloid-beta precursor protein (APP), by common consensus one of the key players in the pathogenesis of Alzheimer’s disease Both the model and the accompanying dataset are open and dynamic in the sense that any element or relationship can be added or discarded by “bringing it forward” from or “sending it back” into “background”, without imposing a judgment as to what is “right” or what is “wrong”. In many cases, the experimental data needed to verify model predictions are already present in research databases
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