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      A Selection of Important Genes and Their Correlated Behavior in Alzheimer’s Disease

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          In 2017, approximately 5 million Americans were living with Alzheimer’s disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected ( FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

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          Most cited references 91

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          TSPLIB—A Traveling Salesman Problem Library

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            hnRNP proteins and the biogenesis of mRNA.

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              Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight.

              Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinson's and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases.

                Author and article information

                Role: Handling Associate Editor
                J Alzheimers Dis
                J. Alzheimers Dis
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                18 July 2018
                7 August 2018
                : 65
                : 1
                : 193-205
                [a ]The Applied Optimization Group/Department of Industrial Engineering, University of Puerto Rico , Mayagüez Campus, Mayagüez, Puerto Rico
                [b ]Department of Basic Science-Biochemistry Division, Ponce Health Sciences University , Ponce, Puerto Rico
                [c ]Public Health Program, Ponce Health Sciences University , Ponce, Puerto Rico
                Author notes
                [* ]Correspondence to: Clara E. Isaza, Public Health Program, Ponce Health Sciences University, Ponce, PR 00732. Tel.: +1 787 840 2575; E-mail: cisaza@ .
                © 2018 – IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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