Computational Interspecies Translation Between Alzheimer’s Disease Mouse Models and Human Subjects Identifies Innate Immune Complement, TYROBP, and TAM Receptor Agonist Signatures, Distinct From Influences of Aging

Mouse models are vital for preclinical research on Alzheimer’s disease (AD) pathobiology. Many traditional models are driven by autosomal dominant mutations identified from early onset AD genetics whereas late onset and sporadic forms of the disease are predominant among human patients. Alongside ongoing experimental efforts to improve fidelity of mouse model representation of late onset AD, a computational framework termed Translatable Components Regression (TransComp-R) offers a complementary approach to leverage human and mouse datasets concurrently to enhance translation capabilities. We employ TransComp-R to integratively analyze transcriptomic data from human postmortem and traditional amyloid mouse model hippocampi to identify pathway-level signatures present in human patient samples yet predictive of mouse model disease status. This method allows concomitant evaluation of datasets across different species beyond observational seeking of direct commonalities between the species. Additional linear modeling focuses on decoupling disease signatures from effects of aging. Our results elucidated mouse-to-human translatable signatures associated with disease: excitatory synapses, inflammatory cytokine signaling, and complement cascade- and TYROBP-based innate immune activity; these signatures all find validation in previous literature. Additionally, we identified agonists of the Tyro3 / Axl / MerTK (TAM) receptor family as significant contributors to the cross-species innate immune signature; the mechanistic roles of the TAM receptor family in AD merit further dedicated study. We have demonstrated that TransComp-R can enhance translational understanding of relationships between AD mouse model data and human data, thus aiding generation of biological hypotheses concerning AD progression and holding promise for improved preclinical evaluation of therapies.

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Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201204 ◽

2021 ◽

Vol 80 (3) ◽

pp. 1151-1168

Author(s):

Barbara Hinteregger ◽

Tina Loeffler ◽

Stefanie Flunkert ◽

Joerg Neddens ◽

Thomas A. Bayer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Mouse Models ◽

Neuronal Degeneration ◽

Integrated Approach ◽

In Vivo Model ◽

Preclinical Research

Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

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Transcriptomic similarities and differences between mouse models and human Alzheimer's Disease

10.1101/2021.06.09.447404 ◽

2021 ◽

Author(s):

Marco Ant&ocircnio De Bastiani ◽

Bruna Bellaver ◽

Giovanna Collar ◽

Stefania Forner ◽

Alessandra Cadete Martini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Mouse Models ◽

Autosomal Dominant ◽

Interaction Analysis ◽

The Novel ◽

Preclinical Research ◽

Similarities And Differences ◽

Transcriptomic Level

Alzheimer's disease (AD) is a multifactorial pathology responsible for most cases of dementia worldwide. Only a small percentage of AD cases are due to autosomal dominant mutations, while the vast majority have a sporadic presentation. Yet, preclinical research studies relied for decades on animal models that overexpress human genes found in AD autosomal dominant patients. Thus, one could argue that these models do not recapitulate sporadic AD. To avoid human gene overexpression artifacts, knock-in (KI) models have been developed, such as the novel hAβ-KI mouse model, which are still in early phases of characterization. We hypothesize that comparisons at the transcriptomic level may elucidate critical similarities and differences between transgenic/KI models and AD patients. Thus, we aimed at comparing the hippocampal transcriptomic profiling of overexpression (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. We first evaluated differentially expressed genes (DEGs) and Gene Ontology biological processes (GOBP) overlapping cross-species. After, we explored a network-based strategy to identify master regulators (MR) and the similarities of such elements among models and AD subtypes. A multiple sclerosis (MS) dataset was included to test the molecular specificity of the mouse models to AD. Our analysis revealed that all three mouse models presented more DEGs, GOBP terms and enriched signaling pathways in common with LOAD than with EOAD subjects. Furthermore, semantic similarity of enriched GOBP terms showed mouse model-specific biological alterations, and protein-protein interaction analysis of DEGs identified clusters of genes exclusively shared between hAβ-KI mice and LOAD. Furthermore, we identified 17 transcription factor candidates potentially acting as MR of AD in all three models. Finally, though all mouse models showed transcriptomic similarities to LOAD, hAβ-KI mice presented a remarkable specificity to this AD subtype, which might support the use of the novel hAβ-KI mouse model to advance our understanding of sporadic LOAD.

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[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

Current Alzheimer Research ◽

10.2174/1567205015666181022095904 ◽

2018 ◽

Vol 16 (1) ◽

pp. 49-55 ◽

Cited By ~ 1

Author(s):

J. Stenzel ◽

C. Rühlmann ◽

T. Lindner ◽

S. Polei ◽

S. Teipel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

New Drugs ◽

Imaging Data ◽

Wild Type ◽

Preclinical Research ◽

Standardized Uptake Values ◽

Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

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A new mouse model to study late-onset Alzheimer’s disease

Lab Animal ◽

10.1038/s41684-021-00780-5 ◽

2021 ◽

Author(s):

Alexandra Le Bras

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Late Onset

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The Innate Immune System in Alzheimer’s Disease

International Journal of Cell Biology ◽

10.1155/2013/576383 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 34

Author(s):

Allal Boutajangout ◽

Thomas Wisniewski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Innate Immune System ◽

Late Onset ◽

Innate Immune ◽

Amyloid Angiopathy ◽

Functional Variant ◽

The Central Nervous System ◽

Congophilic Amyloid Angiopathy

Alzheimer’s disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloidβ(Aβ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

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Hallmarks of late‐onset Alzheimer’s disease in a humanized mouse model

Alzheimer s & Dementia ◽

10.1002/alz.045162 ◽

2020 ◽

Vol 16 (S2) ◽

Author(s):

Kevin P. Kotredes ◽

Christoph Preuss ◽

Ravi S. Pandey ◽

Paul R. Territo ◽

Adrian L. Oblak ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Late Onset ◽

Humanized Mouse ◽

Humanized Mouse Model

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Amyloid precursor protein (APP) knock‐in mouse model recapitulates transciptomic signature in human late‐onset Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.036880 ◽

2020 ◽

Vol 16 (S2) ◽

Author(s):

Marco Antônio De Bastiani ◽

Eduardo R. Zimmer ◽

Stefania Forner ◽

Alessandra Cadete Martini

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Precursor Protein ◽

Late Onset ◽

Precursor Protein

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A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

International Journal of Molecular Sciences ◽

10.3390/ijms222313168 ◽

2021 ◽

Vol 22 (23) ◽

pp. 13168

Author(s):

Natasha Elizabeth Mckean ◽

Renee Robyn Handley ◽

Russell Grant Snell

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Mouse Model ◽

Mouse Models ◽

Small Animal ◽

Large Animal ◽

Complex Disorders ◽

Large Animal Models ◽

The Impact

Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes.

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A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-020-00412-5 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Christoph Preuss ◽

◽

Ravi Pandey ◽

Erin Piazza ◽

Alexander Fine ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Mouse Models ◽

Late Onset ◽

Cost Effective ◽

Common Disease ◽

Disease Genes ◽

Postmortem Human Brain ◽

5Xfad Mouse

Abstract Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer’s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. Results This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. Conclusions Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models.

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