Decoding the Role of Astrocytes in the Entorhinal Cortex in Alzheimer’s Disease Using High-Dimensional Single-Nucleus RNA Sequencing Data and Next-Generation Knowledge Discovery Methodologies: Focus on Drugs and Natural Product Remedies for Dementia

Abstract

Introduction: Alzheimer’s disease (AD) is a major cause of the development of cognitive decline and dementia. AD and associated dementias (ADRD) are the major contributors to the enormous burden of morbidity and mortality worldwide. To date, there are no robust therapies to alleviate or cure this debilitating disease. Most drug treatments focus on restoring the normal function of neurons and the cells that cause inflammation, such as microglia in the brain. However, the role of astrocytes, the brain’s housekeeping cells, in the development of AD and the initiation of dementia is still not well understood.Objective: To decipher the role of astrocytes in the entorhinal cortex of AD patients using single nuclear RNA sequencing (snRNASeq) datasets from the Single Cell RNA-seq Database for Alzheimer’s Disease (scREAD). The datasets were originally derived from astrocytes, isolated from the entorhinal cortex of AD brain and healthy brain to decipher disease-specific signaling pathways as well as drugs and natural products that reverse AD-specific signatures in astrocytes.Methods: We used snRNASeq datasets from the scREAD database originally derived from astrocytes isolated from the entorhinal cortex of AD and healthy brains from the Gene Expression Omnibus (GEO) (GSE138852 and GSE147528) and analyzed them using next-generation knowledge discovery (NGKD) platforms. scREAD is a user-friendly open-source interface available at https://bmbls.bmi.osumc.edu/scread/that enables more discovery-oriented strategies. snRNASeq data and metadata can also be visualized and downloaded via an interactive web application at adsn.ddnetbio.com. Differentially expressed genes (DEGs) for each snRNASeq dataset were analyzed using iPathwayGuide to compare and derive disease-specific pathways, gene ontologies, and in silico predictions of drugs and natural products that regulate AD -specific signatures in astrocytes. In addition, DEGs were analyzed using the L1000FWD and L1000CDS2 signature search programming interfaces (APIs) to identify additional drugs and natural products that mimic or reverse AD-specific gene signatures in astrocytes.Results: We found that PI3K/AKT signaling, Wnt signaling, neuroactive ligand-receptor interaction pathways, neurodegeneration pathways, etc. were significantly impaired in astrocytes from the entorhinal cortex of AD patients. Biological processes such as glutamate receptor signaling pathway, regulation of synapse organization, cell-cell adhesion via plasma membrane adhesion molecules, and chylomicrons were negatively enriched in the astrocytes from the entorhinal cortex of AD patients. Gene sets involved in cellular components such as postsynaptic membrane, synaptic membrane, postsynapse, and synapse part were negatively enriched (p < 0.01). Moreover, molecular functions such as glutamate receptor activity, neurotransmitter receptor activity, and extracellular ligand-gated ion channels were negatively regulated in the astrocytes of the entorhinal cortex of AD patients (p < 0.01). Moreover, the application of NGKD platforms revealed that antirheumatic drugs, vitamin-E, emetine, narciclasine, cephaeline, trichostatin A, withaferin A, dasatinib, etc. can potentially reverse gene signatures associated with AD.Conclusions: The present study highlights an innovative approach to use NGKD platforms to find unique disease-associated signaling pathways and specific synthetic drugs and natural products that can potentially reverse AD and ADRD-associated gene signatures.

Editorial: Methods and application in integrative and regenerative pharmacology: 2021

“…Advances in the field of biomaterials for stem cell and drug delivery in the last decade have given a much-needed boost to the development of regenerative medicine (Sankar et al, 2017;Farokhi et al, 2021;Pishavar et al, 2021;Irfan et al, 2022;Maruthi and Ramakrishna, 2022). The research progress and development in the field of RNA interference (RNAi) and RNA activation (RNAa) (Li et al, 2006;Pushparaj et al, 2008a;Pushparaj et al, 2008b;Li, 2017;Tan et al, 2021), CRISPR-CAS9 gene editing methods, and the potential application of next-generation knowledge discovery platforms in basic and translational research (Pushparaj et al, 2022) in integrative and regenerative pharmacology are essential for the development of personalized therapies (Figure 1).…”

Defining the role of the antineoplastic drug bleomycin based on toxicogenomic-DNA damage inducing (TGx-DDI) genomic biomarkers data: A meta-analysis using next-generation knowledge discovery method

“…The DEGs were further analyzed using iPathwayGuide for NGKD analyzes as previously described. 9 Next Generation Knowledge Discovery using iPathwayGuide: The DEGs were subjected to iPathwayGuide analysis as previously described. 9 The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for the pathway analysis in iPathwayGuide.…”

Exploring Convergent Two‐Step Synthetic Approaches to the Pancratistatin Framework

“…They can target mitochondria in some systems, [4] and have been investigated to relieve postsurgical pain [5] . In addition, they have also been shown to exert anti‐inflammatory effects, [2e,f,6] with possible applications in asthma [7] and as potential treatments for Alzheimer's Disease [8] …”

“…[5] In addition, they have also been shown to exert antiinflammatory effects, [2e,f,6] with possible applications in asthma [7] and as potential treatments for Alzheimer's Disease. [8] Owing to problems of isolation and purification from natural sources, chemical synthesis of the pancratistatin framework has been the subject of much interest. [1,2b,9] An efficient synthetic route could provide access to non-natural analogues with potential for improved drug-like physicochemical proper-ties.…”