Evaluation of animal model congruence to human depression based on large-scale gene expression patterns of the CNS

Gammie, Stephen C.

doi:10.1038/s41598-021-04020-1

Cited by 9 publications

(9 citation statements)

References 70 publications

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“…We recently used a depression portrait to identify animal models with congruence to depression 102 and ongoing useful steps could involve use of the AD portrait (or similar portraits) to evaluate and identify what animal model has the highest concordance with the AD brain signature. Advances in this area have already begun as a recent study identified mouse models that were congruent with coexpression modules found in AD 24 .…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Hill

Gammie

2022

Sci Rep

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

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Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Hill

Gammie

2022

Sci Rep

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“…In the present study, the Ttr gene was found to be increased in both FSS and R-SDS mouse models, and Ttr overexpression induced depression-like behavior as measured by two different tests, the TST and PST. However, it is important to assess how well mouse models match human depression because some mouse models showed no relation to human depression in central nervous system gene expression changes [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to chronic stress, acute stress can induce protein phosphorylation and gene transcription in the hippocampus [ 17 ]. Several animal models for human depression have been used to identify gene expression patterns [ 18 ]. However, comparisons of gene expressions between different depression models or the identification of differentially expressed genes in multiple depression models have been scarcely explored, whereas previous studies have mainly focused on a single model in this context.…”

Section: Introductionmentioning

confidence: 99%

Transthyretin Is Commonly Upregulated in the Hippocampus of Two Stress-Induced Depression Mouse Models

Saito-Takatsuji

Yoshitomi

Yamamoto

et al. 2023

IJMS

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Chronic stress can affect gene expression in the hippocampus, which alters neural and cerebrovascular functions, thereby contributing to the development of mental disorders such as depression. Although several differentially expressed genes in the depressed brain have been reported, gene expression changes in the stressed brain remain underexplored. Therefore, this study examines hippocampal gene expression in two mouse models of depression induced by forced swim stress (FSS) and repeated social defeat stress (R-SDS). Transthyretin (Ttr) was commonly upregulated in the hippocampus of both mouse models, as determined by microarray, RT-qPCR, and Western blot analyses. Evaluation of the effects of overexpressed Ttr in the hippocampus using adeno-associated virus-mediated gene transfer revealed that TTR overexpression induced depression-like behavior and upregulation of Lcn2 and several proinflammatory genes (Icam1 and Vcam1) in the hippocampus. Upregulation of these inflammation-related genes was confirmed in the hippocampus obtained from mice vulnerable to R-SDS. These results suggest that chronic stress upregulates Ttr expression in the hippocampus and that Ttr upregulation may be involved in the induction of depression-like behavior.

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“…In this study, we contribute to on-going work by comparing and ranking expression patterns from 500 animal models with those from human AD. We include the new data from the GFAP mutation mice along with two independently curated model lists; one produced by us (over 300 models) in a study of human depression [ 25 ] and the other from Wan and colleagues (~ 200 models) [ 18 ] in a study of AD. This study focusses on congruence (similarity) of dysregulation in the model and AD (same direction of change) that uses a standardized cutoff and is independent of whether a gene is in a co-expression module or not.…”

Section: Introductionmentioning

confidence: 99%

Large-scale gene expression changes in APP/PSEN1 and GFAP mutation models exhibit high congruence with Alzheimer’s disease

Gammie,

Messing,

Hill

et al. 2024

PLoS ONE

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder with both genetic and non-genetic causes. Animal research models are available for a multitude of diseases and conditions affecting the central nervous system (CNS), and large-scale CNS gene expression data exist for many of these. Although there are several models specifically for AD, each recapitulates different aspects of the human disease. In this study we evaluate over 500 animal models to identify those with CNS gene expression patterns matching human AD datasets. Approaches included a hypergeometric based scoring system that rewards congruent gene expression patterns but penalizes discordant gene expression patterns. The top two models identified were APP/PS1 transgenic mice expressing mutant APP and PSEN1, and mice carrying a GFAP mutation that is causative of Alexander disease, a primary disorder of astrocytes in the CNS. The APP/PS1 and GFAP models both matched over 500 genes moving in the same direction as in human AD, and both had elevated GFAP expression and were highly congruent with one another. Also scoring highly were the 5XFAD model (with five mutations in APP and PSEN1) and mice carrying CK-p25, APP, and MAPT mutations. Animals with the APOE3 and 4 mutations combined with traumatic brain injury ranked highly. Bulbectomized rats scored high, suggesting anosmia could be causative of AD-like gene expression. Other matching models included the SOD1G93A strain and knockouts for SNORD116 (Prader-Willi mutation), GRID2, INSM1, XBP1, and CSTB. Many top models demonstrated increased expression of GFAP, and results were similar across multiple human AD datasets. Heatmap and Uniform Manifold Approximation Plot results were consistent with hypergeometric ranking. Finally, some gene manipulation models, including for TYROBP and ATG7, were identified with reversed AD patterns, suggesting possible neuroprotective effects. This study provides insight for the pathobiology of AD and the potential utility of available animal models.

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Evaluation of animal model congruence to human depression based on large-scale gene expression patterns of the CNS

Cited by 9 publications

References 70 publications

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Transthyretin Is Commonly Upregulated in the Hippocampus of Two Stress-Induced Depression Mouse Models

Large-scale gene expression changes in APP/PSEN1 and GFAP mutation models exhibit high congruence with Alzheimer’s disease

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