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  • 1
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    Creation and designing of PENN Database for natural molecules effective against age related disorders
    VRI Press ; 2014
    In:  Vedic Research International Bioinformatics and Proteomics Vol. 2, No. 1 ( 2014-01-01), p. 1-
    Details
    In: Vedic Research International Bioinformatics and Proteomics, VRI Press, Vol. 2, No. 1 ( 2014-01-01), p. 1-
    Type of Medium: Online Resource
    ISSN: 2330-0272
    URL: Issue
    URL: Article
    DOI: 10.14259/bp.v2i1
    DOI: 10.14259/bp.v2i1.66
    Language: Unknown
    Publisher: VRI Press
    Publication Date: 2014
    detail.hit.zdb_id: 2736964-X
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  • 2
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    Multimodal Imaging of Neurometabolic Pathology due to Traumatic Brain Injury
    Elsevier BV ; 2017
    In:  Trends in Neurosciences Vol. 40, No. 1 ( 2017-01), p. 39-59
    Details
    In: Trends in Neurosciences, Elsevier BV, Vol. 40, No. 1 ( 2017-01), p. 39-59
    Type of Medium: Online Resource
    ISSN: 0166-2236
    URL: Article
    DOI: 10.1016/j.tins.2016.10.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2011000-5
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  • 3
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    Advancing the international data science workforce through shared training and education
    F1000 Research Ltd ; 2019
    In:  F1000Research Vol. 8 ( 2019-3-4), p. 251-
    Details
    In: F1000Research, F1000 Research Ltd, Vol. 8 ( 2019-3-4), p. 251-
    Type of Medium: Online Resource
    ISSN: 2046-1402
    URL: Journal
    URL: Article
    DOI: 10.12688/f1000research
    DOI: 10.12688/f1000research.18357.1
    Language: English
    Publisher: F1000 Research Ltd
    Publication Date: 2019
    detail.hit.zdb_id: 2699932-8
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  • 4
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    Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease
    Cold Spring Harbor Laboratory ; 2022
    In:  Learning & Memory Vol. 29, No. 9 ( 2022-09), p. 321-331
    Details
    In: Learning & Memory, Cold Spring Harbor Laboratory, Vol. 29, No. 9 ( 2022-09), p. 321-331
    Abstract: Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele ( APOE4 ), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3 , APOE3/4 , and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4 , although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.
    Type of Medium: Online Resource
    ISSN: 1549-5485
    URL: Article
    DOI: 10.1101/lm.053588.122
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2022
    detail.hit.zdb_id: 2022057-1
    SSG: 12
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  • 5
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    Translational potential of JAX humanized APOE mice: Metabolism and body composition in very old mice
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Apolipoprotein (APOE) is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Clinically, LOAD exhibits strong sex effects with females being twice at the risk of developing AD than males. Models exhibiting strong AD etiology are used in preclinical settings, however lack of translatability necessitates model development with a reverse translational approach. This study explores metabolic hallmarks of LOAD assessing the clinical translatability of the JAX humanized APOE (hAPOE) mouse model. Method hAPOE mice (M/F, n = 65, mean age = 23.35 +/‐ 0.90 months) with e3/3, e3/4 or e4/4 genotype underwent a metabolic and body composition screening assay including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18 F‐FDG‐PET brain imaging, prior to being sacrificed. Blood plasma was analyzed for triglyceride levels. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum. All data were analyzed with genotype x sex analysis of variance. P ≤ 0.05 was considered statistically significant and post‐hoc pairwise analyses were conducted for interaction effects with p ≤ 0.1 (FKB, adipose index) for future study planning. Result Females had significantly lower lean mass (p 〈 0.0001) and FBG (p=0.05), with a trend toward lower glucose uptake on FDG‐PET compared to males (p=0.072). Post‐hoc interaction analyses of FKB (interaction p=0.105) demonstrated lower ketone body levels in male e4/4s compared to female e4/4s (uncorrected p=0.0685) and male e3/4s (p=0.034). Post‐hoc interaction analyses of adipose index (interaction p=0.093) demonstrated greater adiposity in female e4/4s compared to male e4/4s (uncorrected p=0.005) and female e3/3s (uncorrected p=0.035). No effects of APOE genotype were observed. Conclusion In a mouse cohort at a comparable human age of ∼ 70 years, lower lean mass, fasting blood glucose, and glucose uptake in the brain for female mice indicates ongoing bioenergetic deficits and is corroborated by observations within clinical populations. Greater adiposity in female e4/4s suggests that brain bioenergetic demand is not being met through fat reserves. However, the overall lack of genotypic effects suggests this bioenergetic crisis is not driven by hAPOE in this animal model, limiting clinical translatability. NIA R01AG057931; University of Arizona TBIR (NIH S10 OD025016).
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.068128
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 6
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    Differences in white matter integrity and hippocampal volumetrics across APOE genotype mice: A blinded preliminary study
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Abstract: Genome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer’s disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐ e 4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e 4 carriers in our humanized APOE (hAPOE) LOAD mouse model. Method Six cohorts of APOE e 3 and e 4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016). Result MRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p 〈 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus. Conclusion Outcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.054419
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 7
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    Translational potential of JAX humanized APOE mice: Peripheral interferon gamma induces systemic immuno‐metabolic dysfunction
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S4 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S4 ( 2022-12)
    Abstract: Inflammation is a well‐documented feature of Alzheimer’s disease (AD) in human brain. Previous findings from our group demonstrated upregulated immune transcripts in the AD brain as well as sex differences in immune transcript levels during pre‐clinical midlife aging. Using our humanized APOE mouse model, we identified elevated immune transcripts in the female brain including interferon signaling genes, CD3, CD4, and MHCII. We hypothesized that activation via increased interferon gamma (IFN‐γ) during endocrine aging may disrupt the immune‐metabolic balance in the brain and therefore advance changes in grey and white matter. With this study, we test the hypothesis that increased levels of peripheral IFN‐γ induces genotype dependent immuno‐metabolic changes in the JAX humanized APOE (hAPOE) mouse model. Method To determine the role of IFN‐γ in female midlife aging and AD risk, pre‐menopausal and peri‐menopausal hAPOE mice were intraperitoneally treated with recombinant IFN‐γ for 9 days. Immunophenotyping using multi‐color flow cytometry was conducted microglial reactivity, phagocytosis, neutral lipid content, oxidative stress, and the presence of lymphocytes were determined. Structural and diffusion weighted analysis using MRI was conducted to evaluate grey and white matter structural integrity in the brain. ELISA assays were conducted to assess the presence of beta amyloid 40 and 42 and levels of pro‐inflammatory cytokines. Result IFN‐γ treated animals exhibited upregulation of markers that perpetuate neuroinflammation and white matter catabolism including MHCII, CD8, pHrodo, and BODIPY. Peripheral immune effects were genotype dependent while immune signaling in brain largely exhibited treatment‐dependent effects. Fasting blood glucose levels were significantly increased by IFN‐γ consistent with an accelerated aging profile. Diffusion metrics including mean and radial kurtosis in addition to mean, axial, and radial diffusivity were greater in IFN‐treated animals. Conclusion Peripheral increase of interferon gamma signaling during female endocrine aging in hAPOE mice induced 1) dysfunction of metabolic systems and neuroinflammatory response and 2) decreases in white and grey matter microstructural integrity throughout the brain. These outcomes support the investigation of therapeutic strategies targeting interferon signaling pathways at the earliest stages of midlife aging to reduce risk of AD or delay AD onset.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S4
    DOI: 10.1002/alz.068655
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 8
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    Translational potential of JAX humanized APOE mice: Peripheral biomarkers of pathology
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Alzheimer’s Disease (AD) drives the global rising incidence of neurodegenerative dementia. Disease progression includes cerebral aggregation of amyloid‐beta plaques and immune activation. Many AD animal models carry mutations that cause an early onset of these phenotypes, but the mutations are rare in human populations; most cases are idiopathic and late‐onset AD (LOAD). Another approach utilizing a transgenic APOE animal model may better model clinical populations. APOE4 is the predominant genetic risk factor for LOAD and confers increasing risk for LOAD in allelic fashion, relative to normative APOE3 . This study investigates the JAX humanized APOE knock‐in mouse model of LOAD’s translational potential for peripheral biomarkers of pathology in aged, male and female mice. Method Aged mice of both sexes (23‐25 months old; 39M/37F) with APOE3/3 , APOE3/4 , and APOE4/4 genotypes underwent blood plasma amyloid‐beta (Aß) measurement. A subset of these animals (30M/28F) additionally received peripheral immunophenotyping of whole blood via flow cytometry. Two‐way ANOVA and post‐hoc t‐tests were conducted to determine data significance. Results Female mice had lower Aß42 plasma levels as well as a decreased Aß42/40 ratio, suggesting higher levels of the aggregate‐prone Aß42 protein in the brain, but there were no observed APOE genotype effects. Blood plasma Aß40 levels did not differ by genotype or sex. Whole blood flow cytometry showed an elevation in CD8 + memory T cells in APOE4/4 mice relative to APOE3/3 and APOE3/4 mice. Aged female mice had a peripheral immune cell profile consistent with a more reactive and dysfunctional immune system than genotype‐matched aged males: higher levels of CD11b + B cells, CD4 + helper T cells, and CD8 + cytotoxic T cells along with a lower percentage of naïve CD4 + and CD8 + T cells. Conclusion In mice aged to resemble a ∼70‐year‐old human population, these results suggest increased brain levels of the aggregate‐prone Aß42 isoform and a reactive peripheral immune system in female APOE mice. This sex difference is consistent with the increased prevalence of LOAD in women. However, the specificity of APOE4 genotype effects may define the translational potential of this humanized APOE mouse model of late‐onset Alzheimer’s Disease. Research supported by T32AG061897, R01AG057931, and RF1AG059093 to RDB.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.067815
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 9
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    Translational potential of JAX humanized APOE mice: Hippocampal volume decline in very old mice
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Whole brain and hippocampal atrophy are the most prominent structural features of late‐onset Alzheimer’s disease (LOAD) and are accepted endpoints in many clinical trials. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with the ε4/ε4 genotype associated with the greatest atrophy rates. To date, there is limited hippocampal volume reporting in preclinical APOE models. To assess the translational potential of a humanized APOE (hAPOE) mouse model, we report age, sex, and genotype effects on total brain and hippocampal volume. Method High resolution ex‐vivo MRIs were obtained from two separate cohorts of male and female hAPOE mice (Cohort 1: n =53, 18.47±0.99 months; Cohort 2: n =33, 24.24±0.58 months). A validated mouse brain atlas was used for volumetric analysis. Cohorts were analyzed separately with genotype by sex analyses of variance for total brain volume (sum of all regions in atlas) as well as left and right hippocampal volume as percent of total brain volume. Result In Cohort 1, hAPOEε4/ε4 mice had significantly larger brains than hAPOEε3/ε3s or hAPOEε3/ε4s, with female hAPOEε4/ε4s having the largest brains (p 〈 0.001). Regardless of genotype, females had smaller left (p=0.006) and right (p 〈 0.001) hippocampi relative to males. In Cohort 2, there were no genotype or sex differences in total brain volume. However, left (p=0.044) and right (p=0.034) hippocampal volumes were smaller for hAPOEε4/ε4 mice compared to hAPOEε3/ε4 mice without sex effects. Conclusion Our findings capitalize on a large dataset ( n =88) of high‐resolution MRIs. At 18‐20 months old (∼60 human years), hAPOEε4/ε4 mice had greater total brain volume than comparably aged hAPOEε3/ε3 or hAPOEε3/ε4 mice without hippocampal atrophy. However, hippocampal atrophy was evident when mice were aged to 24‐25 months (∼70 human years). These findings of larger brain volume and greater hippocampal atrophy in hAPOEε4/ε4 carriers are consistent with large‐scale AD imaging datasets. The timing of evident hippocampal atrophy in these mice also coincides with the global average age of clinical diagnosis. Based on these findings, the translational potential of this model requires utilizing very old mice, limiting the window for therapeutic testing. Acknowledgements NIA R01AG057931, RF1AG059093; University of Arizona TBIR (NIH S10 OD025016)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.068141
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 10
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    Mild cognitive impairment and structural brain abnormalities in a sexagenarian with a history of childhood traumatic brain injury
    Wiley ; 2018
    In:  Journal of Neuroscience Research Vol. 96, No. 4 ( 2018-04), p. 652-660
    Details
    In: Journal of Neuroscience Research, Wiley, Vol. 96, No. 4 ( 2018-04), p. 652-660
    Abstract: In this report, we present a case study involving an older, female patient with a history of pediatric traumatic brain injury (TBI). Magnetic resonance imaging and diffusion tensor imaging volumes were acquired from the volunteer in question, her brain volumetrics and morphometrics were extracted, and these were then systematically compared against corresponding metrics obtained from a large sample of older healthy control (HC) subjects as well as from subjects in various stages of mild cognitive impairment (MCI) and Alzheimer disease (AD). Our analyses find the patient's brain morphometry and connectivity most similar to those of patients classified as having early‐onset MCI, in contrast to HC, late MCI, and AD samples. Our examination will be of particular interest to those interested in assessing the clinical course in older patients having suffered TBI earlier in life, in contradistinction to those who experience incidents of head injury during aging.
    Type of Medium: Online Resource
    ISSN: 0360-4012 , 1097-4547
    URL: Issue
    URL: Article
    DOI: 10.1002/jnr.v96.4
    DOI: 10.1002/jnr.24084
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1474904-X
    SSG: 12
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