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Review
. 2017;59(3):1045-1055.
doi: 10.3233/JAD-170255.

Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models

Alpha Tom Kodamullil  1   2 , Anandhi Iyappan  1   2 , Reagon Karki  1   2 , Sumit Madan  1   2 , Erfan Younesi  1 , Martin Hofmann-Apitius  1   2
Affiliations
Review

Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models

Alpha Tom Kodamullil et al. J Alzheimers Dis. 2017.

Abstract

Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species.

Keywords: Alzheimer’s disease; human; mice; neuroinflammation.

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Figures

Fig.1
Fig.1
Workflow used for construction of models and their analysis.
Fig.2
Fig.2
Shared pathways and bioprocess between mouse and human. Entities present in both models are in black color, enriched pathways in mouse are in RED color, enriched pathways in human are in GREEN color.
Fig.3
Fig.3
Cytokine-cytokine receptor interaction (human and mouse). BLACK color indicates interactions are consistent with human, RED color depicts contradictory interactions in mouse compared to human, and BLUE arrows show the interactions found only in human.
Fig.4
Fig.4
Celecoxib interactions in human and mouse. The green lines represent the normal brain interaction of celecoxib targets (Pdpk1 and Ptgs2) with other entities proposed in mouse experiments. The red dotted lines indicate how normal pathways might be perturbed upon administration of celecoxib, which could lead to severity of neuroinflammation and AD. The purple dotted lines are the beneficial effects of celecoxib in the context of AD and neuroinflammation. The black up and down arrows represents the expression of genes (upregulation and downregulation) upon celecoxib administration.
See this image and copyright information in PMC

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