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Background: Despite limited evidence, a high-flow nasal cannula (HFNC) is often used to treat mild to moderate (m/m) bronchiolitis. We aimed to decrease the rate of HFNC use in the pediatric emergency department (PED) for m/m bronchiolitis from a baseline of 37% to less than 18.5%. Methods: A multidisciplinary team created a bronchiolitis pathway and implemented it in December 2019. A respiratory score (RS) in the electronic medical record objectively classified bronchiolitis severity as mild, moderate, or severe. We tracked HFNC utilization in the PED among patients with m/m bronchiolitis as our primary outcome measure between December 2019 and December 2021. We monitored the percentage of patients with an RS as a process measure. Interventions through four plan-do-study-act cycles included updating the hospital oxygen therapy policy, applying the RS to all patients in respiratory distress, modifying the bronchiolitis order set, and developing a bronchiolitis-specific HFNC order. Results: Three hundred twenty-five patients were admitted from the PED with m/m bronchiolitis during the 11-month baseline period and 600 patients during the 25-month intervention period. The mean rate of HFNC utilization decreased from 37% to 17%. Despite a decrease in bronchiolitis encounters after the pandemic, in the spring of 2021, when volumes returned, we had a sustained HFNC utilization rate of 17%. RS entry increased from 60% to 73% in the intervention period. Conclusions: A clinical pathway for bronchiolitis can lead to decreased use of HFNC for m/m bronchiolitis. Consistent RS, order set development with decision support, and education led to sustained improvement despite pandemic-related volumes.
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Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.
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PURPOSE: The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. METHODS: A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. RESULTS: The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. CONCLUSION: The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.
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Neoplasias , Criança , Humanos , Feminino , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Maine , Medicina de Precisão , Oncologia , GenômicaRESUMO
Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer's disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C > T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C > T allele on the C57BL/6J background (Mthfr677C > T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C > T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr677C > T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr677C > T mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
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Metilenotetra-Hidrofolato Redutase (NADPH2) , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Camundongos , Animais , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos Endogâmicos C57BL , Ácido Fólico , Predisposição Genética para Doença , GenótipoRESUMO
Introduction: The interdisciplinary field of bioinformatics is considered an information-based discipline by many. Yet, it is unclear how Master of Library and Information Science (MLIS) degrees prepare librarians to apply their expertise in this unique, often non-textual information environment. The goal of this study is to identify the availability of MLIS-based bioinformatics educational opportunities to provide an update to the current bioinformatics landscape in North American MLIS programs or iSchools. Methods: We conducted a survey of available bioinformatics courses and program concentrations within 69 ALA-accredited master's programs. Using course catalogues and program descriptions on department websites, we identified the existence of courses and concentrations specific or related to the field of bioinformatics. We also surveyed the availability of associated certificate programs or degree alternatives. Results: Only two library and information science (LIS)-based bioinformatics courses are currently offered to MLIS students in ALA-accredited programs. There are no bioinformatics concentrations offered in the programs surveyed, however two graduate certificates could be applied towards an ALA-accredited master's degree. Students interested in related fields can pursue degree alternatives, including eight dual degree options. Discussion: The scarcity of LIS-based bioinformatics courses and program concentrations may suggest that LIS has not adopted bioinformatics into their field nor curricula. As a result, students interested in pursuing careers in bioinformatics and related disciplines must actively seek out opportunities for education and professional development. Bioinformatics degree options within MLIS or iSchools points towards an increased dialogue and acceptance of the connection between bioinformatics and information science, but the lack of ALA -accreditation limits possibilities for emerging librarians.
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Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including complement component 1qa (C1QA) and C3 are increased in the brain of Western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity-induced brain pathology, female and male mice deficient in C1QA, an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared with WD-fed wild type (WT) mice, and to C1qa knock-out (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.
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Complemento C1q , Substância Branca , Animais , Complemento C1q/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade , Substância Branca/metabolismoRESUMO
BACKGROUND: New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer's disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease. METHODS: We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; hemizygous deletions of Bin1 and Cd2ap; and a transgenic APOEε4. Similar data from a transgenic APP/PS1 model was included for comparison to early-onset variant effects. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of correlated genes and each module was tested for differential expression by strain. We then compared mouse modules with human postmortem brain modules from the Accelerating Medicine's Partnership for AD (AMP-AD) to determine the LOAD-related processes affected by each genetic risk factor. RESULTS: Mouse modules were significantly enriched in multiple AD-related processes, including immune response, inflammation, lipid processing, endocytosis, and synaptic cell function. WGCNA modules were significantly associated with Apoe-/-, APOEε4, Clu-/-, and APP/PS1 mouse models. Apoe-/-, GFAP-driven APOEε4, and APP/PS1 driven modules overlapped with AMP-AD inflammation and microglial modules; Clu-/- driven modules overlapped with synaptic modules; and APP/PS1 modules separately overlapped with lipid-processing and metabolism modules. CONCLUSIONS: This study of genetic mouse models provides a basis to dissect the role of AD risk genes in relevant AD pathologies. We determined that different genetic perturbations affect different molecular mechanisms comprising AD, and mapped specific effects to each risk gene. Our approach provides a platform for further exploration into the causes and progression of AD by assessing animal models at different ages and/or with different combinations of LOAD risk variants.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Doença de Alzheimer/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia/metabolismoRESUMO
BACKGROUND: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood. RESULTS: To better understand the effects of exercise, we preformed transcriptional profiling on young (1-2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells. CONCLUSIONS: Taken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.
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Circulação Cerebrovascular , Perfilação da Expressão Gênica , Corrida , Transcriptoma , Remodelação Vascular/genética , Fatores Etários , Animais , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Biologia Computacional/métodos , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Ontologia Genética , Masculino , Camundongos , Modelos Biológicos , Especificidade de Órgãos/genéticaRESUMO
BACKGROUND: Environmental factors are critical in the development of age-related cognitive decline and dementia. A western diet (WD) can cause nutrient deficiency and inflammation that could impact cognition directly. It is increasingly recognized that innate immune responses by brain myeloid cells, such as resident microglia, and infiltrating peripheral monocytes/macrophages may represent an essential link between a WD, cognitive decline, and dementia. Our previous data demonstrated that chronic consumption of a WD induced inflammation through brain myeloid cells in aging mice and a mouse model of Alzheimer's disease (AD). However, the subtypes of myeloid cells that contribute to the WD-induced inflammation remain unclear. METHODS: C57BL/6J (B6), myeloid cell reporter mice (B6.Ccr2RFP/+Cx3cr1GFP/+), and Ccr2-deficient mice (B6.Ccr2RFP/RFP) were fed a WD or a control chow diet (CD) from 2 to 6 or 12 months of age. CD11b+CD45lo and CD11b+CD45hi cells from WD- and CD-fed B6 or Ccr2-deficient mice were characterized using flow cytometry, RNA-sequencing, and immunofluorescence. RESULTS: Ccr2::RFP expressing myeloid cells were significantly increased in brains of WD- compared to CD-fed mice, but were not elevated in Ccr2-deficient WD-fed mice. The percent of CD11b+CD45hi cells was significantly increased in WD- compared to CD-fed mice. Comparison of RNA-sequencing data with immune cell data in ImmGen supports that CD11b+CD45hi cells from WD-fed mice are enriched for peripheral monocytes and neutrophils. Ingenuity pathway analysis predicted these cells elicit proinflammatory responses that may be damaging to the brain. Using stringent criteria for gene expression levels between CD11b+CD45hi and CD11b+CD45lo cells, we identified approximately 70 genes that we predict are uniquely expressed in infiltrating cells, including Itgal, Trem1, and Spp1 (osteopontin, OPN). Finally, we show a significantly greater number of OPN+IBA1- cells in WD- compared to CD-fed mice that we propose are activated neutrophils based on ImmGen data. OPN+IBA1- cells are not significantly increased in Ccr2-deficient WD-fed mice. CONCLUSIONS: These data further support the model that peripheral myeloid cells enter the brain in response to diet-induced obesity. Elucidating their contribution to age-related cognitive decline and age-related neurodegenerative diseases should offer new avenues for therapeutic intervention in Alzheimer's disease and related dementias, where diet/obesity are major risk factors.
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Antígeno CD11a/metabolismo , Dieta Ocidental/efeitos adversos , Perfilação da Expressão Gênica/métodos , Obesidade/metabolismo , Osteopontina/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/metabolismo , Obesidade/induzido quimicamente , Obesidade/genética , Osteopontina/genética , Receptor Gatilho 1 Expresso em Células Mieloides/genéticaRESUMO
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.
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Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Exercício Físico/fisiologia , Leucoencefalopatias/prevenção & controle , Obesidade/complicações , Condicionamento Físico Animal/fisiologia , Animais , Humanos , Inflamação , Leucoencefalopatias/patologia , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Oligodendroglia/patologia , Substância Branca/citologia , Substância Branca/patologiaRESUMO
Evidence suggests that multiple genetic and environmental factors conspire together to increase susceptibility to Alzheimer's disease (AD). The amyloid cascade hypothesis states that deposition of the amyloid-ß (Aß) peptide is central to AD; however, evidence in humans and animals suggests that Aß buildup alone is not sufficient to cause neuronal cell loss and cognitive decline. Mouse models that express high levels of mutant forms of amyloid precursor protein and/or cleaving enzymes deposit amyloid but do not show neuron loss. Therefore, a double-hit hypothesis for AD has been proposed whereby vascular dysfunction precedes and promotes Aß toxicity. In support of this, copy number variations in mesenchyme homeobox 2 (MEOX2), a gene involved in vascular development, are associated with severe forms of AD. However, the role of MEOX2 in AD has not been studied. Here, we tested Meox2 haploinsufficiency in B6.APP/PS1 (B6.APB(Tg)) mice, a mouse model of AD. Despite no overt differences in plaque deposition or glial activation, B6.APB(Tg) mice that carry only one copy of Meox2 (B6.APB(Tg).Mx(-/+)) show increased neuronal cell loss, particularly in regions containing plaques, compared with B6.APB(Tg) mice. Neuronal cell loss corresponds with a significant decrease in plaque-associated microvessels, further supporting a synergistic effect of vascular compromise and amyloid deposition on neuronal cell dysfunction in AD.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Neurônios/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Memória EspacialRESUMO
Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer's disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased in APP/PS1 mice fed the western diet. This increase in glial responses was associated with increased plaque burden in the hippocampus. Interestingly, given recent studies highlighting the importance of TREM2 in microglia/monocytes in AD susceptibility and progression, B6 and APP/PS1 mice fed the western diet showed significant increases TREM2+ microglia/monocytes. Therefore, an increase in TREM2+ microglia/monocytes may underlie the increased risk from a western diet to age-related neurodegenerative diseases such as Alzheimer's disease. This study lays the foundation to fully investigate the impact of a western diet on glial responses in aging and Alzheimer's disease.
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Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Dieta Ocidental/efeitos adversos , Gliose/metabolismo , Microglia/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Gliose/genética , Gliose/patologia , Camundongos , Camundongos Transgênicos , Microglia/patologiaRESUMO
Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer's disease.
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Envelhecimento , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Complemento C1q/metabolismo , Atividade Motora , Doenças Neurodegenerativas/prevenção & controle , Doenças Vasculares/prevenção & controle , Animais , Apolipoproteínas E/sangue , Apolipoproteínas E/química , Apolipoproteínas E/genética , Astrócitos/imunologia , Astrócitos/patologia , Astrócitos/ultraestrutura , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/ultraestrutura , Ativação do Complemento , Complemento C1q/genética , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homozigoto , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Monócitos/ultraestrutura , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Plasticidade Neuronal , Acoplamento Neurovascular , Estabilidade Proteica , Doenças Vasculares/imunologia , Doenças Vasculares/metabolismo , Doenças Vasculares/patologiaRESUMO
Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition.
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Encéfalo/metabolismo , Síndrome de Down/genética , Feto/metabolismo , Transcriptoma/genética , Animais , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Fenótipo , Gravidez , Regulação para Cima/genéticaRESUMO
Alzheimer's disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.
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Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Amiloide/metabolismo , Progressão da Doença , Convulsões/complicações , Convulsões/patologia , Envelhecimento/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cromossomos de Mamíferos/genética , Complemento C5/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Microglia/patologia , Mutagênese Insercional , Neurônios/patologia , Fenótipo , Placa Amiloide/patologia , Presenilinas/metabolismo , TransgenesRESUMO
Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.
Assuntos
Doença de Alzheimer/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Fatores Etários , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Antígenos Comuns de Leucócito/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Camundongos Transgênicos , Receptores Imunológicos/genética , Regulação para Cima , Proteínas tau/metabolismoRESUMO
BACKGROUND: Alzheimer's disease affects more than 35 million people worldwide but there is no known cure. Age is the strongest risk factor for Alzheimer's disease but it is not clear how age-related changes impact the disease. Here, we used a mouse model of Alzheimer's disease to identify age-specific changes that occur prior to and at the onset of traditional Alzheimer-related phenotypes including amyloid plaque formation. To identify these early events we used transcriptional profiling of mouse brains combined with computational approaches including singular value decomposition and hierarchical clustering. RESULTS: Our study identifies three key events in early stages of Alzheimer's disease. First, the most important drivers of Alzheimer's disease onset in these mice are age-specific changes. These include perturbations of the ribosome and oxidative phosphorylation pathways. Second, the earliest detectable disease-specific changes occur to genes commonly associated with the hypothalamic-adrenal-pituitary (HPA) axis. These include the down-regulation of genes relating to metabolism, depression and appetite. Finally, insulin signaling, in particular the down-regulation of the insulin receptor substrate 4 (Irs4) gene, may be an important event in the transition from age-related changes to Alzheimer's disease specific-changes. CONCLUSION: A combination of transcriptional profiling combined with computational analyses has uncovered novel features relevant to Alzheimer's disease in a widely used mouse model and offers avenues for further exploration into early stages of AD.
Assuntos
Doença de Alzheimer/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Transcriptoma , Doença de Alzheimer/genética , Animais , Córtex Cerebral/metabolismo , Análise por Conglomerados , Modelos Animais de Doenças , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/metabolismo , Fenótipo , Sistema Hipófise-Suprarrenal/metabolismo , Transdução de Sinais , Transcrição GênicaAssuntos
Álcoois/química , Ouro/química , Nanopartículas Metálicas/química , Paládio/química , Catálise , OxirreduçãoRESUMO
BACKGROUND: Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex. METHODS: To assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence. RESULTS: C5-sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina. CONCLUSION: C5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma.