scholarly journals Downregulation of ATP6V1A Involved in Alzheimer’s Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Zhike Zhou ◽  
Jun Bai ◽  
Shanshan Zhong ◽  
Rongwei Zhang ◽  
Kexin Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Phosphorylation ◽  
Synaptic Vesicle ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Functional Enrichment ◽  
Gabaergic Synapse ◽  
Vesicle Cycle ◽  
Synaptic Vesicle Cycle

Objective. The objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer’s disease (AD). Methods. Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. Results. The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. Conclusions. Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Screening novel drug candidates for Alzheimer’s disease by an integrated network and transcriptome analysis

2020 ◽  
Vol 36 (17) ◽  
pp. 4626-4632
Author(s):  
Yonglin Peng ◽  
Meng Yuan ◽  
Juncai Xin ◽  
Xinhua Liu ◽  
Ju Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Supplementary Information ◽  
Integrated Network ◽  
Drug Candidates ◽  
Novel Drug

Abstract Motivation Alzheimer’s disease (AD) is a serious degenerative brain disease and the most common cause of dementia. The current available drugs for AD provide symptomatic benefit, but there is no effective drug to cure the disease. The emergence of large-scale genomic, pharmacological data provides new opportunities for drug discovery and drug repositioning as a promising strategy in searching novel drug for AD. Results In this study, we took advantage of our increasing understanding based on systems biology approaches on the pathway and network levels and perturbation datasets from the Library of Integrated Network-Based Cellular Signatures to introduce a systematic computational process to discover new drugs implicated in AD. First, we collected 561 genes that have reported to be risk genes of AD, and applied functional enrichment analysis on these genes. Then, by quantifying proximity between 5595 molecule drugs and AD based on human interactome, we filtered out 1092 drugs that were proximal to the disease. We further performed an Inverted Gene Set Enrichment analysis on these drug candidates, which allowed us to estimate effect of perturbations on gene expression and identify 24 potential drug candidates for AD treatment. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a useful systematic method, our approach can also be used to identify efficacious therapies for other complex diseases. Availability and implementation The source code is available at https://github.com/zer0o0/drug-repo.git. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals IPSC-derived neuronal cultures expressing the Alzheimer’s disease associated rare TREM2 R47H variant enables the construction of an Aβ-induced gene regulatory network

2019 ◽  
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
Kristel Sleegers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory

AbstractRecently, genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer’s disease (LOAD). One of them is the rare p.Arg47His (R47H) variant within triggering receptor expressed on myeloid cells 2 (TREM2), which has been shown to increase the risk for developing AD 2-3-fold. Here, we report the generation and characterization of a model of LOAD using lymphoblast-derived iPSCs from patients harbouring the R47H mutation in TREM2 (AD TREM2 iPSCs), as well as from control individuals without dementia (CON iPSCs). iPSCs efficiently differentiate into mature neuronal cultures and comparative global transcriptome analysis identified a distinct gene expression profile in AD TREM2 neuronal cultures. Furthermore, manipulation of the iPSC-derived functional neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD TREM2 neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER) which emphasised ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

scholarly journals IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network

2020 ◽  
Vol 21 (12) ◽  
pp. 4516
Author(s):  
Soraia Martins ◽  
Andreas Müller-Schiffmann ◽  
Lars Erichsen ◽  
Martina Bohndorf ◽  
Wasco Wruck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Cultures ◽  
Gene Regulatory ◽  
Induced Pluripotent

Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer’s disease (AD) 2–3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer’s disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

2019 ◽  
Vol 19 (4) ◽  
pp. 216-223 ◽  
Author(s):  
Tianyi Zhao ◽  
Donghua Wang ◽  
Yang Hu ◽  
Ningyi Zhang ◽  
Tianyi Zang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Feature Vector ◽  
Mirna Gene ◽  
Interaction Network ◽  
Gene Interaction ◽  
Proteinprotein Interaction ◽  
Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

scholarly journals Transcriptome analyses of 7-day-old zebrafish larvae possessing a familial Alzheimer’s disease-like mutation in psen1 indicate effects on oxidative phosphorylation, ECM and MCM functions, and iron homeostasis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yang Dong ◽  
Morgan Newman ◽  
Stephen M. Pederson ◽  
Karissa Barthelson ◽  
Nhi Hin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Phosphorylation ◽  
Transcriptome Analysis ◽  
Iron Homeostasis ◽  
Late Onset ◽  
Wild Type ◽  
Familial Alzheimer’S Disease ◽  
Zebrafish Larvae ◽  
Familial Alzheimer's Disease

Abstract Background Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. Results We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed various bioinformatics analyses to predict cellular functions. Conclusions Our analyses predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Genes related to extracellular matrix (ECM) were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3′ untranslated regions (UTRs). These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

scholarly journals Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

2021 ◽  
Vol 10 (8) ◽  
pp. 1555
Author(s):  
Ágoston Patthy ◽  
János Murai ◽  
János Hanics ◽  
Anna Pintér ◽  
Péter Zahola ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Brain Structures ◽  
Specific Information ◽  
Cellular Mechanisms ◽  
Monoaminergic System ◽  
Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

Sign in / Sign up

Export Citation Format

Share Document