Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

Chami, Mounia

doi:10.3390/cells10010140

Cited by 12 publications

(6 citation statements)

References 35 publications

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“…In CN samples, interestingly, among the most signi cant pathways enriched with signi cant CpGs is the KEGG pathway "Alzheimer's disease", which was curated based on recent AD literature and included genes that confer AD risks, such as APOE, PSENEN, MAPT, CALM3, MME, and others. Also, in CN samples, the most signi cant pathway is the calcium signaling pathway (P-value = 2.39 × 10 − 4 , FDR = 9.09 × 10 − 3 ), consistent with the calcium hypothesis of AD, which posits that dysregulated neuronal calcium homeostasis induces impaired synaptic plasticity, defective neurotransmission, promotes accumulation of Aβ and tau proteins, and subsequently lead to neuronal apoptosis in the brain 98,99 . Moreover, increased levels of free intracellular calcium have also been observed in normal aging, the strongest risk factor for AD 100,101 .…”

Section: Discussionsupporting

confidence: 66%

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

Zhang

Young

Gomez

et al. 2023

Preprint

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Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Methods We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. Results We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. Conclusions Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.

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Section: Discussionsupporting

confidence: 66%

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

Zhang

Young

Gomez

et al. 2023

Preprint

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“…Therefore, research on the pathogenesis of existing diseases can be used to guide future research on the neural circuit mechanisms of OCD. At pres- ent, research on neurodegenerative diseases such as Alzheimer's disease is relatively mature, with many related mechanism studies; [10][11][12][13] therefore, research on the mechanism of OCD has a high reference value.…”

Section: Discussionmentioning

confidence: 99%

Informational Analysis and Prediction of Obsessive-Compulsive Disorder Pathogenesis

Wang,

Zhang

et al. 2024

Psychiatry Investig

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Objective We aimed to predict the possible mechanism of obsessive-compulsive disorder (OCD) by integrating and analyzing mRNA sequencing results from two datasets and to provide direction for future studies into the pathogenesis of OCD.Methods Two OCD datasets, GSE78104 and GSE60190, were obtained, and the intersection of the two gene sets with differential expression in OCD samples was selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment and Gene Ontology (GO) analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) online analysis website for the genes at the intersection, and the data were mapped using http://www.bioinformatics.com.cn. After genes with p≤0.05 had been screened out, protein-protein interaction (PPI) interaction analysis was conducted using Metascape to screen the key Molecular Complex Detection (MCODE) genes. MCODE genes were then enriched using the KEGG signaling pathway and GO classification.Results A total of 3,449 differentially expressed genes (DEGs) were obtained from the GSE78104 and GSE60190 datasets. KEGG, GO, and Gene Set Enrichment Analysis analyses of DEGs showed that the onset of OCD was related to oxidative phosphorylation and other metabolic processes, which may have a similar pathogenesis to other neurodegenerative diseases. Single-gene PPI analysis of SAPAP3 revealed that the mechanism by which SAPAP3 knockout induces OCD may also be caused by affecting oxidative phosphorylation.Conclusion The mechanism of SAPAP3 knockout-induced OCD in mice may be due to the oxidative phosphorylation process in the body. Future studies on the neural circuit mechanism of OCD should be conducted.

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“…It has recently been proposed that the Aβ small oligomers may penetrate [54] and aggregate within the membrane, forming unregulated and heterogeneous ion channels [55][56][57] which would allow ion dyshomeostasis [58], leading to cellular degeneration. In this context, it is useful to remind the reader that numerous studies [59][60][61] underline the important role of neuronal Ca 2+ dyshomeostasis in AD. A recent investigation [62] showed that oxidized membranes are prone to form native and oxidized domains which can induce a poration process [63].…”

Section: Discussionmentioning

confidence: 99%

Oxidation of Phospholipids by OH Radical Coordinated to Copper Amyloid-β Peptide—A Density Functional Theory Modeling

Rovetta,

Carosella,

Arrigoni

et al. 2023

Inorganics

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Oxidative stress and metal dyshomeostasis are considered crucial factors in the pathogenesis of Alzheimer’s disease (AD). Indeed, transition metal ions such as Cu(II) can generate reactive oxygen species (ROS) via O2 Fenton-like reduction, catalyzed by Cu(II) coordinated to the amyloid-beta (Aβ) peptide. Despite intensive efforts, the mechanisms of ROS-induced molecular damage remain poorly understood. In the present paper, we investigate, on the basis of Density Functional Theory (DFT) computations, a possible mechanism of the OH radical propagation toward membrane phospholipid polar head and fatty acid chains starting from the end-product of the OH radical generation by Cu(II)-Aβ. Using phosphatidylcholine as a model of a single unit inside a membrane, we evaluated the thermochemistry of the OH propagation with the oxidation of a C-H bond and the formation of the radical moiety. The DFT results show that Cu(II)-Aβ-OH can oxidize only sn-2 C-H bonds of the polar head and can easily oxidize the C-H bond adjacent to the carbon–carbon double bond in a mono or bis unsaturated fatty acid chain. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications in the AD oxidative stress mechanism.

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Calcium Signalling in Alzheimer’s Disease: From Pathophysiological Regulation to Therapeutic Approaches

Abstract: Alzheimer’s disease (AD) is a neurodegenerative pathology representing a socioeconomic challenge, however, the complex mechanism behind the disease is not yet fully understood [...]

Cited by 12 publications

References 35 publications

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

Distinct CSF biomarker-associated DNA methylation in Alzheimer's disease and cognitively normal subjects

Informational Analysis and Prediction of Obsessive-Compulsive Disorder Pathogenesis

Oxidation of Phospholipids by OH Radical Coordinated to Copper Amyloid-β Peptide—A Density Functional Theory Modeling

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