Browsing by Author "Howell, Gareth R."

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    Aging x Environment x genetic risk for late onset Alzheimer’s disease results in alterations in cognitive function in mice independent of amyloid and tau pathology
    (Wiley, 2025-01-03) Williams, Sean-Paul Gerard; Santos, Diogo Francisco Silva; Haynes, Kathryn A.; Heaton, Nicholas; Hart, Jason T.; Kotredes, Kevin P.; Pandey, Ravi S.; Persohn, Scott C.; Eldridge, Kierra; Ingraham, Cynthia M.; Lloyd, Christopher D.; Wang, Nian; Sasner, Michael; Carter, Gregory W.; Territo, Paul R.; Lamb, Bruce T.; Howell, Gareth R.; Oblak, Adrian L.; Sukoff Rizzo, Stacey J.; Neurology, School of Medicine
    Background: Alzheimer’s disease (AD) research has been historically dominated with studies in mouse models expressing familial AD mutations; however, the majority of AD patients have the sporadic, late‐onset form of AD (LOAD). To address this gap, the IU/JAX/PITT MODEL‐AD Consortium has focused on development of mouse models that recapitulate LOAD by combining genetic risk variants with environmental risk factors and aging to enable more precise models to evaluate potential therapeutics. The present studies were undertaken to characterize cognitive and neurophysiological phenotypes in LOAD mice. Method: Two genetic risk factors, APOE4 and Trem2*R47H, were incorporated into C57BL/6J mice with humanized amyloid‐beta to produce the LOAD2 model (JAX# 030670). Male and female LOAD2 and WT mice were exposed to ad libitum 45% high‐fat diet from 2‐months of age (LOAD2+HFD or WT+HFD, respectively) throughout their lifespan and compared to LOAD2 and WT mice on control diet (+CD). Cognitive training began at 14‐months of age using a touchscreen testing battery, similar to previously described methods (Oomen et al 2013). At the conclusion of touchscreen testing, subjects were implanted with wireless telemetry devices (DSI) for evaluation of electroencephalography (EEG) signatures. Result: All subjects met the touch‐reward association criteria. During task acquisition LOAD2+CD mice demonstrated impaired acquisition relative to WT+CD, while both LOAD2+HFD and WT+HFD failed to learn the task as indicated by accuracy less than chance (<50%); which was confirmed in a separate cohort. LOAD2+HFD mice demonstrated increased spikewave events as measured by EEG, relative to LOAD2+CD. At 18‐months of age +CD mice that met acquisition criteria were evaluated in a location discrimination task with LOAD2+CD mice demonstrating modest impairments in pattern separation relative to age‐matched WT+CD. Conclusion: These data are the first reports of cognitive deficits and neurophysiological alterations in mice with environmental x genetic risk for LOAD, independent of amyloid and tau pathology. Importantly, the present findings demonstrate the sensitivity of the translational touchscreen testing battery for detecting mild cognitive impairment in LOAD mice with corresponding neurophysiologic alterations, and extend previous characterization data for the LOAD2 model and its utility for the study of the biology of LOAD.
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    Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction
    (Wiley, 2024) Onos, Kristen D.; Lin, Peter B.; Pandey, Ravi S.; Persohn, Scott A.; Burton, Charles P.; Miner, Ethan W.; Eldridge, Kierra; Nyandu Kanyind, Jonathan; Foley, Kate E.; Carter, Gregory W.; Howell, Gareth R.; Territo, Paul R.; Neurology, School of Medicine
    Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.
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    Assessment of Neurovascular Uncoupling: APOE Status is a Key Driver of Early Metabolic and Vascular Dysfunction
    (bioRxiv, 2024-03-13) Onos, Kristen; Lin, Peter B.; Pandey, Ravi S.; Persohn, Scott A.; Burton, Charles P.; Miner, Ethan W.; Eldridge, Kierra; Nyandu Kanyinda, Jonathan; Foley, Kate E.; Carter, Gregory W.; Howell, Gareth R.; Territo, Paul R.; Neurology, School of Medicine
    Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 mo, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 mo, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifest as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.
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    Characterization of the A1527G variant of ABCA7 in an animal model for late‐onset Alzheimer’s disease
    (Wiley, 2025-01-03) Bernabe, Cristian S.; Kotredes, Kevin P.; Pandey, Ravi S.; Carter, Gregory W.; Sasner, Michael; Oblak, Adrian L.; Howell, Gareth R.; Lamb, Bruce T.; Territo, Paul R.; MODEL-AD consortium; Medicine, School of Medicine
    Background: Genome‐wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known. Method: The IU/JAX/PITT MODEL‐AD Center identified the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was first used to introduce Abca7*A1527G variant to B6.APOE4.Trem2*R47H (LOAD1) mice to assess the transcriptional profiling on brain hemispheres from different ages. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb (LOAD2) mice to further evaluate its contribution to LOAD. Female and male LOAD2.Abca7*A1527G and LOAD2 mice were characterized at 4, 12, and 24 months using the following phenotyping pipeline: behavior, PET/CT, multi‐omics, fluid biomarkers, electrophysiology, cognition, and neuropathology. Result: Brain transcriptional profiling showed that Abca7*A1527G induced changes in gene expression that are similar to some of those observed in human AD (e.g., granulocyte/neutrophil migration, and insulin receptor signaling). LOAD2.Abca7*A1527G showed no aging cognitive deficit but did show significant sex‐ and region‐dependent increases in brain glycolysis paralleled by reduced tissue perfusion yielding progressive age‐related uncoupled phenotypes between 4‐12 and 4‐24 months. While multi‐resolution consensus clustering of regional covariance matrices revealed an increase in cluster number and organization in LOAD2.Abca7*A1527G over LOAD2 for both sexes at 4 months, the cluster number and complexity were reduced by 24 months. Importantly, LOAD2.Abca7*A1527G, but not LOAD2, displayed a similar age‐dependent reduction in cluster number for both sexes. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma with genotype, but were not age dependent. Conversely, brain levels of IL4, IL12, TNFα, and CXCL1 were decreased, whereas IL2 and IL10 were elevated in LOAD2.Abca7*A1527G relative to LOAD2. Lastly, assessment of plasma levels of Ab40‐Ab42 revealed an age‐dependent increase in both genotypes. Conclusion: Data collected to date support a model whereby variations in ABCA7 exert risk for AD through interactions between cerebrovasculature, microglia, and peripheral immune cells.
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    Characterizing Molecular and Synaptic Signatures in mouse models of Late-Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology
    (bioRxiv, 2023-12-20) Kotredes, Kevin P.; Pandey, Ravi S.; Persohn, Scott; Elderidge, Kierra; Burton, Charles P.; Miner, Ethan W.; Haynes, Kathryn A.; Santos, Diogo Francisco S.; Williams, Sean-Paul; Heaton, Nicholas; Ingraham, Cynthia M.; Lloyd, Christopher; Garceau, Dylan; O’Rourke, Rita; Herrick, Sarah; Rangel-Barajas, Claudia; Maharjan, Surendra; Wang, Nian; Sasner, Michael; Lamb, Bruce T.; Territo, Paul R.; Sukoff Rizzo, Stacey J.; Carter, Gregory W.; Howell, Gareth R.; Oblak, Adrian L.; Medical and Molecular Genetics, School of Medicine
    Introduction: MODEL-AD is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to more accurately mimic LOAD than commonly used transgenic models. Methods: We created the LOAD2 model by combining APOE4, Trem2*R47H, and humanized amyloid-beta. Mice aged up to 24 months were subjected to either a control diet or a high-fat/high-sugar diet (LOAD2+HFD) from two months of age. We assessed disease-relevant outcomes, including in vivo imaging, biomarkers, multi-omics, neuropathology, and behavior. Results: By 18 months, LOAD2+HFD mice exhibited cortical neuron loss, elevated insoluble brain Aβ42, increased plasma NfL, and altered gene/protein expression related to lipid metabolism and synaptic function. In vivo imaging showed age-dependent reductions in brain region volume and neurovascular uncoupling. LOAD2+HFD mice also displayed deficits in acquiring touchscreen-based cognitive tasks. Discussion: Collectively the comprehensive characterization of LOAD2+HFD mice reveal this model as important for preclinical studies that target features of LOAD independent of amyloid and tau.
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    Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study
    (Frontiers Media, 2021-07-23) Oblak, Adrian L.; Lin, Peter B.; Kotredes, Kevin P.; Pandey, Ravi S.; Garceau, Dylan; Williams, Harriet M.; Uyar, Asli; O’Rourke, Rita; O’Rourke, Sarah; Ingraham, Cynthia; Bednarczyk, Daria; Belanger, Melisa; Cope, Zackary A.; Little, Gabriela J.; Williams, Sean-Paul G.; Ash, Carl; Bleckert, Adam; Ragan, Tim; Logsdon, Benjamin A.; Mangravite, Lara M.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Carter, Gregory W.; Howell, Gareth R.; Sasner, Michael; Lamb, Bruce T.; Radiology and Imaging Sciences, School of Medicine
    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.
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    Contributions of heavy metal exposure to late‐onset Alzheimer’s disease
    (Wiley, 2025-01-03) Kotredes, Kevin P.; Minaeva, Olga; Pandey, Ravi S.; Moncaster, Juliet A.; Lamb, Bruce T.; Carter, Gregory W.; Goldstein, Lee E.; Howell, Gareth R.; Medical and Molecular Genetics, School of Medicine
    Background: Late‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants‐LOAD association is known, the molecular mechanisms modulated by these gene‐environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD‐associated brain pathologies in next‐generation mouse models of LOAD. Examination of these gene‐environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis. Method: Young and aged mice from novel polygenic strains expressing LOAD risk alleles (APOE4, Trem2, APP, Mthfr, Abca7) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP‐mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human‐aligned, LOAD‐related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD‐relevant phenotypes, including amyloid burden, glial activity, and neuron loss. Result: Neurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD‐relevant genes in a toxicant‐specific manner, including a decrease in Vgf and an increase in App. Reduced VGF expression has been observed and reported in all four independent AMP‐AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated. Conclusion: Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.
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    Corrigendum: Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
    (Frontiers Media, 2022-02-07) Kotredes, Kevin P.; Oblak, Adrian; Pandey, Ravi S.; Lin, Peter Bor-Chian; Garceau, Dylan; Williams, Harriet; Uyar, Asli; O’Rourke, Rita; O’Rourke, Sarah; Ingraham, Cynthia; Bednarczyk, Daria; Belanger, Melisa; Cope, Zackary; Foley, Kate E.; Logsdon, Benjamin A.; Mangravite, Lara M.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Carter, Gregory W.; Sasner, Michael; Lamb, Bruce T.; Howell, Gareth R.; Pharmacology and Toxicology, School of Medicine
    An author name was incorrectly spelled as “Daria Bednarycek”. The correct spelling is “Daria Bednarczyk”. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
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    Distinct mouse models correspond to distinct AD molecular subtypes
    (Wiley, 2025-01-03) Pandey, Ravi S.; Carter, Gregory W.; Howell, Gareth R.; Sasner, Michael; Kotredes, Kevin P.; Oblak, Adrian L.; Lamb, Bruce T.; Pharmacology and Toxicology, School of Medicine
    Background: Alzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Mouse models of AD serve as indispensable platforms for comprehensively characterizing AD pathology, disease progression, and biological mechanisms. However, selection of the right model in preclinical research and translation of findings to clinical populations are intricate processes that require identification of pathophysiological resemblance between model organisms and humans. Many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study had consisted of a heterogeneous group of participants, and individual animal models may only recapitulate features of a subgroup of human cases. To improve interspecies translation, it is necessary to comprehensively compare molecular signatures in mouse models with subgroup of human AD cases with distinct molecular signatures. Method: We performed transcriptomic and proteomics analysis on whole brain samples from mouse models carrying LOAD risk variants. To assess the human disease relevance of LOAD risk variants in mice, we determined the extent to which changes due to genetic perturbations in mice matched those observed in human AD subtypes and disease stages of AD in the ROS/MAP, Mayo and Mount Sinai Brain Bank cohorts. Genesets within these disease subtypes are highly co‐expressed and represent specific molecular pathways. Result: We have identified that distinct mouse models match to distinct human AD subtypes in age‐dependent manner. Specifically, mouse models carrying human AD risk variants such as Abca7*A1527G showed strong correlation with inflammatory AD subtypes, while mouse models carrying risk variant such as Plcg2*M28L exhibited transcriptomics changes similar to non‐inflammatory AD subtypes. Conclusion: In this study, we highlighted that mouse model of AD may match to a particular subset of human AD subtypes but not all subtypes simultaneously, and that risk for these subtypes may be influenced by distinct AD genetic factors. Additional work toward validating and better understanding the role of each subtype key regulator in its matching mouse model will provide great value and have a great impact on future studies of AD.
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    Exercise prevents obesity-induced cognitive decline and white matter damage in mice
    (Elsevier, 2019-08) Graham, Leah C.; Grabowska, Weronika A.; Chun, Yoona; Risacher, Shannon L.; Philip, Vivek M.; Saykin, Andrew J.; Sukoff Rizzo, Stacey J.; Howell, Gareth R.; Radiology and Imaging Sciences, School of Medicine
    Obesity in the western world has reached epidemic proportions, and yet the long-term effects on brain health are not well understood. To address this, we performed transcriptional profiling of brain regions from a mouse model of western diet (WD)-induced obesity. Both the cortex and hippocampus from C57BL/6J (B6) mice fed either a WD or a control diet from 2 months of age to 12 months of age (equivalent to midlife in a human population) were profiled. Gene set enrichment analyses predicted that genes involved in myelin generation, inflammation, and cerebrovascular health were differentially expressed in brains from WD-fed compared to control diet-fed mice. White matter damage and cerebrovascular decline were evident in brains from WD-fed mice using immunofluorescence and electron microscopy. At the cellular level, the WD caused an increase in the numbers of oligodendrocytes and myeloid cells suggesting that a WD is perturbing myelin turnover. Encouragingly, cerebrovascular damage and white matter damage were prevented by exercising WD-fed mice despite mice still gaining a significant amount of weight. Collectively, these data show that chronic consumption of a WD in B6 mice causes obesity, neuroinflammation, and cerebrovascular and white matter damage, but these potentially damaging effects can be prevented by modifiable risk factors such as exercise.