From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes.

Muthusankar Aathi

doi:10.6026/97320630015760

Abstract

Successive oxidative stress and biochemical changes results in neuronal death and neuritic plaques growth in Alzheimer's disease (AD). Therefore, it is interest to analyze amyloid-βeta precursor protein (APP), beta-secretase 1 (BACE1), presenilin (PSEN1 and PSEN2) genes from brain tissues to gain insights. Development of potential inhibitors for these targets is of significance. EST sequences of 2898 (APP), 539 (BACE1), 786 (PSEN1) and 314 (PSEN2) genes were analyzed in this study. A contig sequences with APP (contigs 1-4), BACE1 (contigs 5-7), PSEN1 (contigs 8, 9, 10, 11), PSEN2 (contigs 13, 14) except PSEN1 (contigs 10) and PSEN2 (contigs 13) genes were identified. APP (contig 3 without translational error) was further analyzed using molecular modeling and docking to show its binding with curcumin (principal curcuminoid of turmeric) having -7.3 kcal/mol interaction energy for further consideration as a potential inhibitor.

Highlights

Alzheimer’s disease (AD) is caused due to the structural and functional loss of neurons which shows symptoms like cognitive and memory deterioration, progressive destruction of intellectual activities in day to life and behavioral abnormalities [1]
Subsequent oxidative stress and biochemical changes result in the neuronal death and development of neuritic plaques in AD [6]
Retrieval of ESTs sequence and assembly: In silico analysis of AD human genes amyloid-βeta precursor protein (APP), beta-secretase 1 (BACE1), PSEN1 and PSEN2 taken from UniGene database and those genes originating from brain tissues were taken

Summary

Introduction

Alzheimer’s disease (AD) is caused due to the structural and functional loss of neurons which shows symptoms like cognitive and memory deterioration, progressive destruction of intellectual activities in day to life and behavioral abnormalities [1]. Alzheimer’s disease is mainly caused due to the accumulation of β-amyloid peptides [5], which are formed by the action of sequential cleaving of the APP gene which plays an important role in the central nervous system. Proteolytic cleavage of APP by β- and γ-secretase enzymes resulting in the release of neurotoxic Aβ peptides which can aggregate into oligomer is known. Mutations in the PSEN1 and PSEN2 genes (which are components of the γ-secretase complex) results in increased cleavage by γsecretase at this site. Both these conditions result in the excess production of Aβ peptide. Subsequent oxidative stress and biochemical changes result in the neuronal death and development of neuritic plaques in AD [6]

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Conclusion