Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice

Downs, A. M. R.; Catavero, Christina M.; Kasten, Michael R.; McElligott, Zoé A.

doi:10.1101/2022.07.22.501151

Cited by 2 publications

(2 citation statements)

References 95 publications

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“…Prior to our study, only two investigations tracked changes in LC activity using rodent AD models, one with Aβ and one with mutant P301S tau pathology [24, 59]. Mislocalization of GABA receptors associated with soluble Aβ oligomers in the LC led to hyperactivity, whereas effects of P301S tau expression were minimal.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer’s disease

Kelberman

Rorabaugh

Anderson

et al. 2022

Preprint

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Accumulation of hyperphosphorylated tau in the locus coeruleus (LC) is a ubiquitous feature of prodromal Alzheimers disease (AD), and LC neurons degenerate as AD progresses. Tau-mediated LC dysfunction may contribute to early neuropsychiatric symptoms, while loss of LC integrity is associated with conversion to cognitive impairment. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons have not been described. The purpose of this study was to characterize changes in firing properties of LC neurons when they are the only cells containing hyperphosphorylated tau, as well as later in disease when β-amyloid (Aβ) and tau pathology is abundant in the forebrain. Single unit LC activity was recorded from anesthetized wild-type (WT) and TgF344-AD rats, which carry the APP/PS1 transgene. Similar to human AD, these rats develop hyperphosphorylated tau in the LC (at 6 months) prior to Aβ or tau pathology in forebrain regions (at 12-15 months). At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates, but showed elevated spontaneous bursting properties, particularly in younger animals. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and aged transgenic rats showing hypoactivity relative to WT. Tau-induced alterations in LC firing rates may contribute to the pathophysiology of AD, with early hyperactivity associated with prodromal symptoms, followed by hypoactivity contributing to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

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Section: Discussionmentioning

confidence: 99%

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer’s disease

Kelberman

Rorabaugh

Anderson

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…AD, along with vascular dementia, constitutes the majority of dementia cases. Cognitive decline in later life has been linked to long-term alcohol consumption, AD, and vascular dementia (Downs et al, 2023;Marsland et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

Tian

Shen

et al. 2023

Front. Aging Neurosci.

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BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease whose origins have not been universally accepted. Numerous studies have demonstrated the relationship between AD and alcohol dependence; however, few studies have combined the origins of AD, alcohol dependence, and programmed cell death (PCD) to analyze the mechanistic relationship between the development of this pair of diseases. We demonstrated in previous studies the relationship between psychiatric disorders and PCD, and in the same concerning neurodegeneration-related AD, we found an interesting link with the Ferroptosis pathway. In the present study, we explored the bioinformatic interactions between AD, alcohol dependence, and Ferroptosis and tried to elucidate and predict the development of AD from this aspect.MethodsWe selected the Alzheimer’s disease dataset GSE118553 and alcohol dependence dataset GSE44456 from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were gathered through Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and relevant literature, resulting in a total of 88 related genes. For the AD and alcohol dependence datasets, we conducted Limma analysis to identify differentially expressed genes (DEGs) and performed functional enrichment analysis on the intersection set. Furthermore, we used ferroptosis-related genes and the DEGs to perform machine learning crossover analysis, employing Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify candidate immune-related central genes. This analysis was also used to construct protein-protein interaction networks (PPI) and artificial neural networks (ANN), as well as to plot receiver operating characteristic (ROC) curves for diagnosing AD and alcohol dependence. We analyzed immune cell infiltration to explore the role of immune cell dysregulation in AD. Subsequently, we conducted consensus clustering analysis of AD using three relevant candidate gene models and examined the immune microenvironment and functional pathways between different subgroups. Finally, we generated a network of gene-gene interactions and miRNA-gene interactions using Networkanalyst.ResultsThe crossover of AD and alcohol dependence DEG contains 278 genes, and functional enrichment analysis showed that both AD and alcohol dependence were strongly correlated with Ferroptosis, and then crossed them with Ferroptosis-related genes to obtain seven genes. Three candidate genes were finally identified by machine learning to build a diagnostic prediction model. After validation by ANN and PPI analysis, ROC curves were plotted to assess the diagnostic value of AD and alcohol dependence. The results showed a high diagnostic value of the predictive model. In the immune infiltration analysis, functional metabolism and immune microenvironment of AD patients were significantly associated with Ferroptosis. Finally, analysis of target genes and miRNA-gene interaction networks showed that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4.ConclusionWe obtained a diagnostic prediction model with good effect by comprehensive analysis, and validation of ROC in AD and alcohol dependence data sets showed good diagnostic, predictive value for both AD (AUC 0. 75, CI 0.91–0.60), and alcohol dependence (AUC 0.81, CI 0.95–0.68). In the consensus clustering grouping, we identified variability in the metabolic and immune microenvironment between subgroups as a likely cause of the different prognosis, which was all related to Ferroptosis function. Finally, we discovered that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4.

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Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice

Cited by 2 publications

References 95 publications

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer’s disease

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer’s disease

Bioinformatics analysis and prediction of Alzheimer’s disease and alcohol dependence based on Ferroptosis-related genes

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