In Silico Analysis to Link Insulin Resistance, Obesity and Ageing with Alzheimer's Disease.

Priyanka Sarkar,Yash Somaiya,Kavitha Thirumurugan,Sourajit Das,Rajagopal Desikan,Ketaki Patwardhan,Samiksha Yeole,Premkumar Jayaraj

doi:10.1007/s12031-021-01875-x

Priyanka Sarkar, Yash Somaiya + Show 6 more

Open Access

https://doi.org/10.1007/s12031-021-01875-x

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Abstract

The process of ageing accompanies several metabolic diseases. With ageing, fats accumulate to increase the visceral and abdominal adiposity leading to hyperinsulinemia, insulin resistance, obesity and several other diseases. Drosophila melanogaster is often used to study the ageing process and its related disorders. Therefore, in this study, we performed an in silico analysis to relate the process of ageing and insulin resistance. We analysed the data of insulin-resistant Drosophila from the GEO database and compared it with the data from the literature survey. We observed that 98 genes were common in both the models, and they showed gene modulations related to metabolic pathways, fatty acid metabolism, insulin resistance and neural receptor-ligand binding pathways. Analysis of the REACTOME database against human data revealed that the TRKB signalling pathway is commonly affected. The TRKB-mediated BDNF pathway is a major regulator of memory loss. We further analysed the common genes in Alzheimer's disease and compared the fly data with human data to identify the diseases related to these common genes. Then, we performed a literature survey to provide protective mechanisms for the TRKB signalling pathway activation, mediated through polyphenols. We treated the flies with sesamol-conjugated lipoic acid derivative (a phenolic compound) at hormetic doses to evaluate its effect on the memory of flies.

Highlights

Ageing is an irreversible process of multicellular organisms and unicellular organisms
Normal ageing is accompanied by fat deposition and lipid accumulation in the abdomen and visceral compartments leading to age enhanced insulin resistance or hyperinsulinemia (Ryan 2000; Refaie et al 2006)
The data obtained from the literature survey and Gene Expression Omnibus (GEO) database revealed 482 genes that are differentially expressed during the process of aging and insulin resistance during obesity lead to the modulation of 1267 genes

Summary

Introduction

Ageing is an irreversible process of multicellular organisms and unicellular organisms. Scientific community is researching and adding hypotheses to elaborate on the cellular and molecular machinery of ageing. Recent research in this field has made it progressively clear that ageing is due to the build-up of molecular damage, which gives a unified theory of ageing. For decades drosophila has been used as a model organism to study ageing and age-related diseases. D.melanogaster has been widely used in genetic research and is a preferred model organism in developmental biology studies (Deepa Parvathi V, Akshaya Amritha S 2009). Pathways like malonate–acetate, shikimic acid, and isoprenoid are involved in polyphenol production They have proven therapeutic effects against several pathological conditions, including neurodegenerative diseases (Stewart and Stewart 2008). Sesamol mitigates memory impairment and causes neuroprotection via activation of Nrf, NFκB and BDNF (Kumar et al 2010; Liu et al 2017, 2018; Ren et al 2018)

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