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

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

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

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

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 Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

2021 ◽  
Vol 13 ◽  
Author(s):  
Adrian L. Oblak ◽  
Peter B. Lin ◽  
Kevin P. Kotredes ◽  
Ravi S. Pandey ◽  
Dylan Garceau ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Mouse Model ◽  
Biochemical Characterization ◽  
Late Onset ◽  
Therapeutic Interventions ◽  
Preclinical Testing ◽  
5Xfad Mouse

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer’s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.

scholarly journals β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Daniel C. Shippy ◽  
Connor Wilhelm ◽  
Patel A. Viharkumar ◽  
Thomas J. Raife ◽  
Tyler K. Ulland
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Ketone Bodies ◽  
Late Onset ◽  
Inflammasome Activation ◽  
Age Related ◽  
Nlrp3 Inflammasome Activation ◽  
5Xfad Mouse

Abstract Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

P4-028: CHARACTERIZING THE APOE4/TREM2*R47H MOUSE MODEL FOR LATE ONSET ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_27) ◽  
pp. P1444-P1444
Author(s):  
Harriet M. Williams ◽  
Adrian L. Oblak ◽  
Rita O'Rourke ◽  
Rebecca Buchanan ◽  
Kelly J. Keezer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Late Onset

Circadian wheel running behavior is altered in an APP/E4 mouse model of late onset Alzheimer's disease

2017 ◽  
Vol 182 ◽  
pp. 137-142 ◽  
Author(s):  
Katelyn N. Boggs ◽  
Peter A. Kakalec ◽  
Meghann L. Smith ◽  
Stefanie N. Howell ◽  
Jane M. Flinn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Wheel Running ◽  
Late Onset

scholarly journals Age-Related Neuronal Deterioration Specifically Within the Dorsal CA1 Region of the Hippocampus in a Mouse Model of Late Onset Alzheimer’s Disease

2021 ◽  
Vol 79 (4) ◽  
pp. 1547-1561
Author(s):  
Rasha H. Mehder ◽  
Brian M. Bennett ◽  
R. David Andrew
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Peroxidation ◽  
Mouse Model ◽  
Oxidative Damage ◽  
Late Onset ◽  
Dendritic Morphology ◽  
Ca1 Region ◽  
Age Related

Background: Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective: We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods: Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results: The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion: This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory.

scholarly journals P2-131: NOVEL APOE4.TREM2*R47H MOUSE MODEL: A BETTER TOOL FOR LATE-ONSET ALZHEIMER'S DISEASE

2019 ◽  
Vol 15 ◽  
pp. P622-P623
Author(s):  
Kevin P. Kotredes ◽  
Christoph Preuss ◽  
Ravi S. Pandey ◽  
Harriet M. Williams ◽  
Paul R. Territo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Late Onset
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