Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer’s Disease Model Mice

2022 ◽  
pp. 1-22
Author(s):  
Guillermo Eastman ◽  
Elizabeth R. Sharlow ◽  
John S. Lazo ◽  
George S. Bloom ◽  
José R. Sotelo-Silveira
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Ribosome Profiling ◽  
Mouse Strains ◽  
Translational Efficiency ◽  
Rna Seq ◽  
Cellular Mechanisms

Background: Defining cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

scholarly journals Transcriptional and translational regulation of pathogenesis in Alzheimer’s disease model mice

2021 ◽  
Author(s):  
Guillermo Eastman ◽  
Elizabeth R. Sharlow ◽  
John S. Lazo ◽  
George S. Bloom ◽  
José R. Sotelo-Silveira
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcriptional Regulation ◽  
Translational Regulation ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Ribosome Profiling ◽  
Translational Efficiency ◽  
Rna Seq

ABSTRACTBackgroundDefining the cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and the ensuing periods of steadily declining cognition. Previous studies have emphasized changes in transcriptional regulation, but not translational regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.ObjectiveTo identify genes whose expression might be regulated at the transcriptional, and especially at the translational levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2-/-) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling).MethodsIdentical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptional and translational levels separately, and also at the translational efficiency level. Regulated genes were functionally evaluated by gene ontology tools.ResultsCompared to WT mice, AD model mice had similar levels of transcriptional regulation, but displayed differences in translational regulation. A specific microglial signature associated with early stages of Aβ accumulation was up-regulated at both transcriptome and translatome levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to APP metabolism associated with neurotoxicity and neuroprotection.ConclusionThis work represents the first genome-wide study of brain translational regulation in animal models of AD, and provides evidence of a tight and early translational regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

P4-253: MULTI-OMICS PROFILING IDENTIFIES APOE-ALLELE-ASSOCIATED LIPID AND GENE EXPRESSION PATTERNS IN ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_29) ◽  
pp. P1543-P1543
Author(s):  
Iliya Lefterov ◽  
Nicholas F. Fitz ◽  
Cody M. Wolfe ◽  
Kyong Nyon Nam ◽  
Florent Letronne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Apoe Allele

scholarly journals Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer's disease

2014 ◽  
Vol 35 (9) ◽  
pp. 1961-1972 ◽  
Author(s):  
Nicole C. Berchtold ◽  
Marwan N. Sabbagh ◽  
Thomas G. Beach ◽  
Ronald C. Kim ◽  
David H. Cribbs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Brain Gene Expression

scholarly journals Nutrigenomic Studies on the Ameliorative Effect of Enzyme-Digested Phycocyanin in Alzheimer’s Disease Model Mice

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4431
Author(s):  
Yasuyuki Imai ◽  
Yurino Koseki ◽  
Makoto Hirano ◽  
Shin Nakamura
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Oral Administration ◽  
Expression Patterns ◽  
Disease Model ◽  
Neuroprotective Effects ◽  
Aberrant Expression ◽  
Ameliorative Effect

Alzheimer’s disease (AD) is the most common form of dementia, and the cognitive impairments associated with this degenerative disease seriously affect daily life. Nutraceuticals for the prevention or delay of AD are urgently needed. It has been increasingly observed that phycocyanin (PC) exerts neuroprotective effects. AD model mice intracerebroventricularly injected with amyloid beta-peptide 25–35 (Aβ25–35) at 10 nmol/head displayed significant cognitive impairment in the spontaneous alternation test. Cognitive impairment was significantly ameliorated in mice treated with 750 mg/kg of enzyme-digested (ED) PC by daily oral administration for 22 consecutive days. Application of DNA microarray data on hippocampal gene expression to nutrigenomics studies revealed that oral EDPC counteracted the aberrant expression of 35 genes, including Prnp, Cct4, Vegfd (Figf), Map9 (Mtap9), Pik3cg, Zfand5, Endog, and Hbq1a. These results suggest that oral administration of EDPC ameliorated cognitive impairment in AD model mice by maintaining and/or restoring normal gene expression patterns in the hippocampus.

scholarly journals Generally applicable transcriptome-wide analysis of translational efficiency using anota2seq

2017 ◽  
Author(s):  
Christian Oertlin ◽  
Julie Lorent ◽  
Valentina Gandin ◽  
Carl Murie ◽  
Laia Masvidal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Analytical Methods ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Translation Regulation ◽  
Translational Efficiency ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Mtor Inhibition

ABSTRACTmRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated results in various disorders. Optimal and universally applicable analytical methods to study transcriptome-wide changes in translational efficiency are therefore critical for understanding the complex role of translation regulation under physiological and pathological conditions. Techniques used to interrogate translatomes, including polysome- and ribosome-profiling, require adjustment for changes in total mRNA levels to capture bona fide alterations in translational efficiency. Herein, we present the anota2seq algorithm for such analysis using data from ribosome- or polysome-profiling quantified by DNA-microarrays or RNA sequencing, which outperforms current methods for identification of changes in translational efficiency. In contrast to available analytical methods, anota2seq also allows capture of an underappreciated mode for regulation of gene expression whereby translation acts as a buffering mechanism which maintains constant protein levels despite fluctuations in mRNA levels (“translational buffering”). Application of anota2seq shows that insulin affects gene expression at multiple levels, in a largely mTOR-dependent manner. Moreover, insulin induces levels of a subset of mRNAs independently of mTOR that undergo translational buffering upon mTOR inhibition. Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes and enables studies of translational buffering which represents an unexplored mechanism for regulating of gene expression.

scholarly journals Regulation of gene expression during the fasting-feeding cycle of the liver displays mouse strain specificity

2020 ◽  
Vol 295 (15) ◽  
pp. 4809-4821 ◽  
Author(s):  
Yuling Chi ◽  
Dou Yeon Youn ◽  
Alus M. Xiaoli ◽  
Li Liu ◽  
Jacob B. Pessin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Nutrient Status ◽  
Mouse Strains ◽  
Strain Specificity ◽  
Biological Regulation ◽  
Lipogenic Genes ◽  
Feeding Cycle

The liver maintains metabolic homeostasis by integrating the regulation of nutrient status with both hormonal and neural signals. Many studies on hepatic signaling in response to nutrients have been conducted in mice. However, no in-depth study is currently available that has investigated genome-wide changes in gene expression during the normal physiological fasting-feeding cycle in nutrient-sensitive and -insensitive mice. Using two strains of mice, C57BL/6J and BALB/cJ, and deploying deep RNA-Seq complemented with quantitative RT-PCR, we found that feeding causes substantial and transient changes in gene expression in the livers of both mouse strains. The majority of significantly changed transcripts fell within the areas of biological regulation and cellular and metabolic processes. Among the metabolisms of three major types of macronutrients (i.e. carbohydrates, proteins, and lipids), feeding affected lipid metabolism the most. We also noted that the C57BL/6J and BALB/cJ mice significantly differed in gene expression and in changes in gene expression in response to feeding. In both fasted and fed states, both mouse strains shared common expression patterns for about 10,200 genes, and an additional 400–600 genes were differentially regulated in one strain but not the other. Among the shared genes, more lipogenic genes were induced upon feeding in BABL/cJ than in C57BL/6J mice. In contrast, in the population of differentially enriched genes, C57BL/6J mice expressed more genes involved in lipid metabolism than BALB/cJ mice. In summary, these results reveal that the two mouse strains used here exhibit several differences in feeding-induced hepatic responses in gene expression, especially in lipogenic genes.

A Qualitative Analysis Based on Relative Expression Orderings Identifies Transcriptional Subgroups for Alzheimer’s Disease

2020 ◽  
Vol 16 (13) ◽  
pp. 1175-1182 ◽  
Author(s):  
Guini Hong ◽  
Pengming Zeng ◽  
Na Li ◽  
Hao Cai ◽  
You Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Region ◽  
Expression Patterns ◽  
Brain Regions ◽  
Gene Expression Patterns ◽  
Relative Expression ◽  
Age Related ◽  
Relative Expression Orderings

Background: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. However, few studies have investigated the heterogeneous gene expression patterns in AD. Objective and Methods: We examined the gene expression patterns in four brain regions of AD based on the within-sample relative expression orderings (REOs). Gene pairs with significantly reversed REOs in AD samples compared to non-AD controls were identified for each brain region using Fisher’s exact test, and filtered according to their transcriptional differences between AD samples. Subgroups of AD were classified by cluster analysis. Results: REO-based gene expression profiling analyses revealed that transcriptional differences, as well as distinct disease subsets, existed within AD patients. For each brain region, two main subgroups were classified: one subgroup reported differentially expressed genes overlapped with the age-related genes, and the other might relate to neuroinflammation. Conclusion: AD transcriptional subgroups might help understand the underlying pathogenesis of AD, and lend support to a personalized approach to AD management.

scholarly journals Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues

2007 ◽  
Vol 313 (3) ◽  
pp. 450-461 ◽  
Author(s):  
Ashani T. Weeraratna ◽  
Audrey Kalehua ◽  
Isoke DeLeon ◽  
Dorothy Bertak ◽  
Gregory Maher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Patterns ◽  
Gene Expression Patterns

scholarly journals Ribosome profiling elucidates the contribution of differential translation to differential gene expression in bundle sheath and mesophyll cells in maize

2020 ◽  
Author(s):  
Prakitchai Chotewutmontri ◽  
Alice Barkan
Keyword(s):  
Gene Expression ◽  
Differential Gene Expression ◽  
Translational Control ◽  
C4 Photosynthesis ◽  
Bundle Sheath ◽  
Ribosome Profiling ◽  
Translational Efficiency ◽  
M Cells ◽  
Rna Seq ◽  
Differential Gene

The efficiencies offered by C4 photosynthesis have motivated efforts to understand its biochemical, genetic and developmental basis. Reactions underlying C4 traits in most C4 plants are partitioned between two cell types, bundle sheath (BS) and mesophyll (M) cells. RNA-seq has been used to catalog differential gene expression in BS and M cells in maize and several other C4 species. However, the contribution of translational control to maintaining the distinct proteomes of BS and M cells has not been addressed. In this study, we used ribosome profiling (ribo-seq) and RNA-seq to describe translatomes, translational efficiencies, and microRNA abundance in BS and M-enriched fractions of maize seedling leaves. A conservative interpretation of our data revealed 39 genes exhibiting cell-type dependent differences in translational efficiency, fourteen of which encode proteins with core roles in C4 photosynthesis. Use of more relaxed criteria that are widely used in ribo-seq studies increased the set of differentially translated genes to several hundred. In addition, our data expand the set of genes known to be differentially expressed in BS and M cells, including genes encoding transcription factors and microRNAs. These data add to the resources for understanding the evolutionary and developmental basis of C4 photosynthesis and for its engineering into C3 crops.

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