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

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.

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

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
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, [<sup>18</sup>F]-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 [<sup>18</sup>F]-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 [<sup>18</sup>F]-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 [<sup>18</sup>F]-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 [<sup>18</sup>F]-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 [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

scholarly journals In Vivo Imaging Biomarkers in Mouse Models of Alzheimer's Disease: Are We Lost in Translation or Breaking Through?

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Benoît Delatour ◽  
Stéphane Epelbaum ◽  
Alexandra Petiet ◽  
Marc Dhenain
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Imaging Biomarkers ◽  
Preclinical Research ◽  
Disease Modifier ◽  
Fundamental Research ◽  
Neuroimaging Biomarkers ◽  
Lost In Translation

Identification of biomarkers of Alzheimer's Disease (AD) is a critical priority to efficiently diagnose the patients, to stage the progression of neurodegeneration in living subjects, and to assess the effects of disease-modifier treatments. This paper addresses the development and usefulness of preclinical neuroimaging biomarkers of AD. It is today possible to image in vivo the brain of small rodents at high resolution and to detect the occurrence of macroscopic/microscopic lesions in these species, as well as of functional alterations reminiscent of AD pathology. We will outline three different types of imaging biomarkers that can be used in AD mouse models: biomarkers with clear translational potential, biomarkers that can serve as in vivo readouts (in particular in the context of drug discovery) exclusively for preclinical research, and finally biomarkers that constitute new tools for fundamental research on AD physiopathogeny.

scholarly journals 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

2021 ◽  
Vol 15 ◽  
Author(s):  
Meelim J. Lee ◽  
Chuangqi Wang ◽  
Molly J. Carroll ◽  
Douglas K. Brubaker ◽  
Bradley T. Hyman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Models ◽  
Late Onset ◽  
Innate Immune ◽  
Cytokine Signaling ◽  
Preclinical Research ◽  
Human Patient ◽  
Receptor Family

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.

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

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.

scholarly journals Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer’s disease-associated markers in 3xTg-AD mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Minesh Kapadia ◽  
M. Firoz Mian ◽  
Donglai Ma ◽  
Craig P. Hutton ◽  
Amber Azam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Emotional Reactivity ◽  
Histone Variant ◽  
In Vivo Model ◽  
Adult Males ◽  
Bdnf Expression ◽  
Systemic Autoimmunity ◽  
Circulating Autoantibodies

Abstract Background Circulating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model. Methods Young 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration. Results Chronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors. Conclusion The results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

In Vivo Perturbation of Lysosomal Function Promotes Neurodegeneration in the PS1M146V/APPK670N,M671L Mouse Model of Alzheimer's Disease Pathology

2003 ◽  
pp. 687-695 ◽  
Author(s):  
Ralph A. Nixon ◽  
Paul M. Mathews ◽  
Anne M. Cataldo ◽  
Panaiyur S. Mohan ◽  
Stephen D. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Lysosomal Function ◽  
Model Of Alzheimer’S Disease
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