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BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.
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COVID-19 , Endosomas , Lisosomas , Tetraspanina 24 , Animales , Lisosomas/metabolismo , Tetraspanina 24/metabolismo , Tetraspanina 24/genética , Humanos , Ratones , COVID-19/metabolismo , COVID-19/inmunología , COVID-19/patología , Endosomas/metabolismo , Ratones Noqueados , Vasculitis/metabolismo , Ratones Endogámicos C57BL , SARS-CoV-2 , Inflamación/metabolismo , Inflamación/patología , Sepsis/metabolismoRESUMEN
17α-estradiol (17α-E2) is a naturally occurring nonfeminizing diastereomer of 17ß-estradiol that has life span-extending effects in rodent models. To date, studies of the systemic and tissue-specific benefits of 17α-E2 have largely focused on the liver, brain, and white adipose tissue with far less focus on skeletal muscle. Skeletal muscle has an important role in metabolic and age-related disease. Therefore, this study aimed to determine whether 17α-E2 treatment has positive, tissue-specific effects on skeletal muscle during a high-fat feeding. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a high-fat diet (HFD) with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in diacylglycerol (DAG) and ceramide content. To test this hypothesis, we used a multiomics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked, but different, beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAG), and inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and ß-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. Although female mice were resistant to HFD-induced changes in DAGs, 17α-E2 treatment induced the upregulation of six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, ß-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate the metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi tissue health span benefits.NEW & NOTEWORTHY Using a multiomics approach, we show that 17α-E2 alleviates HFD-induced metabolic detriments in skeletal muscle by altering bioactive lipid intermediates, inflammatory cytokines, and the abundance of proteins related to lipolysis and muscle contraction. The positive effects of 17α-E2 in skeletal muscle occur in both sexes but differ in their outcome.
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Dieta Alta en Grasa , Estradiol , Animales , Masculino , Femenino , Ratones , Estradiol/farmacología , Estradiol/metabolismo , Dieta Alta en Grasa/efectos adversos , Diglicéridos/metabolismo , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Ratones Endogámicos C57BLRESUMEN
OBJECTIVES: To better understand the experiences of Black pregnant women during COVID-19, we examined Black pregnant clients' and doulas' experiences with perinatal support services amid COVID-19's social distancing protocols. METHODS: We used qualitative description, employing a social constructionist framework to interview 12 perinatal support doulas and 29 Black women who were pregnant or gave birth during the pandemic about their experiences during the pandemic, when social distancing was required. RESULTS: Three key themes were identified: (1) Clients experienced increased social isolation; (2) Doulas' exclusion from medical visits limited women's access to support and advocacy; (3) Doula support as a sisterhood helped clients mitigate effects of COVID isolation. CONCLUSIONS FOR PRACTICE: Doulas should be considered essential support persons for Black pregnant women and should not be excluded from the birthing team. Support through technology is acceptable for some clients but less desirable for others and restricted doula's ability to build rapport and be hands on with their clients.
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COVID-19 , Doulas , Servicios de Salud Materna , Femenino , Humanos , Embarazo , COVID-19/epidemiología , Relaciones Interpersonales , Parto , Negro o AfroamericanoRESUMEN
AIMS: This study examined the nature and characteristics of Black women's interactions with medical providers during childbirth when accompanied by a perinatal support professional (PSP; similar to a doula). DESIGN: The design was qualitative, and a phenomenological approach was employed to examine the meaning of women's experiences. METHODS: We conducted in-depth interviews with 25 Black women enrolled in a perinatal support program in Cleveland, Ohio, in late 2017 and early 2018, exploring their interactions with medical providers, the meaning of their experiences, and the roles their PSPs played. RESULTS: Clients broadly categorized experiences as positive or negative. When medical providers respected them, their birth plans and/or collaborated with PSPs, women reported more positive experiences. They associated negative experiences with providers having their own timelines and agendas, and women perceiving their needs were unheard and/or disrespected. CONCLUSION: The findings emphasize the need for medical providers to be patient-centred, set aside assumptions, treat their patients as experts, value women's knowledge and voice, and treat patients and their supports as part of the team. IMPACT: Findings support the importance of having a knowledgeable but non-medical support person present during birth. We discuss implications for how empowerment may be a tool to achieving better birth outcomes.
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Doulas , Parto , Parto Obstétrico , Emociones , Femenino , Humanos , Ohio , Embarazo , Investigación CualitativaRESUMEN
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by extracellular plaques containing amyloid ß (Aß)-protein and intracellular tangles containing hyperphosphorylated Tau protein. Here, we describe the generation of inducible pluripotent stem cell lines from patients harboring the London familial AD (fAD) amyloid precursor protein (APP) mutation (V717I). We examine AD-relevant phenotypes following directed differentiation to forebrain neuronal fates vulnerable in AD. We observe that over differentiation time to mature neuronal fates, APP expression and levels of Aß increase dramatically. In both immature and mature neuronal fates, the APPV717I mutation affects both ß- and γ-secretase cleavage of APP. Although the mutation lies near the γ-secretase cleavage site in the transmembrane domain of APP, we find that ß-secretase cleavage of APP is elevated leading to generation of increased levels of both APPsß and Aß. Furthermore, we find that this mutation alters the initial cleavage site of γ-secretase, resulting in an increased generation of both Aß42 and Aß38. In addition to altered APP processing, an increase in levels of total and phosphorylated Tau is observed in neurons with the APPV717I mutation. We show that treatment with Aß-specific antibodies early in culture reverses the phenotype of increased total Tau levels, implicating altered Aß production in fAD neurons in this phenotype. These studies use human neurons to reveal previously unrecognized effects of the most common fAD APP mutation and provide a model system for testing therapeutic strategies in the cell types most relevant to disease processes.
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Enfermedad de Alzheimer/mortalidad , Péptidos beta-Amiloides/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Humanos , Neuronas/citología , Neuronas/metabolismo , Proteínas tau/genéticaRESUMEN
Recent memories are generally recalled from a first-person perspective whereas older memories are often recalled from a third-person perspective. We investigated how repeated retrieval affects the availability of visual information, and whether it could explain the observed shift in perspective with time. In Experiment 1, participants performed mini-events and nominated memories of recent autobiographical events in response to cue words. Next, they described their memory for each event and rated its phenomenological characteristics. Over the following three weeks, they repeatedly retrieved half of the mini-event and cue-word memories. No instructions were given about how to retrieve the memories. In Experiment 2, participants were asked to adopt either a first- or third-person perspective during retrieval. One month later, participants retrieved all of the memories and again provided phenomenology ratings. When first-person visual details from the event were repeatedly retrieved, this information was retained better and the shift in perspective was slowed.
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Imaginación/fisiología , Memoria Episódica , Recuerdo Mental/fisiología , Percepción Visual/fisiología , Adulto , Humanos , Adulto JovenRESUMEN
Neuronal precursor cell migration in the developing mammalian brain is a complex process requiring the coordinated interaction of numerous proteins. We have recently shown that amyloid precursor protein (APP) plays a role in migration into the cortical plate through its interaction with two cytosolic signaling proteins, disabled 1 (DAB1) and disrupted in schizophrenia 1 (DISC1). In order to identify extracellular factors that may signal through APP to regulate migration, we performed an unbiased mass spectrometry-based screen for factors that bind to the extracellular domain of APP in the rodent brain. Through this screen, we identified an interaction between APP and pancortins, proteins expressed throughout the developing and mature cerebral cortex. Via co-immunoprecipitation, we show that APP interacts with all four of the mammalian pancortin isoforms (AMY, AMZ, BMY, BMZ). We demonstrate that the BMZ and BMY isoforms of pancortin can specifically reduce ß-secretase- but not α-secretase-mediated cleavage of endogenous APP in cell culture, suggesting a biochemical consequence of the association between pancortins and APP. Using in utero electroporation to overexpress and knock down specific pancortin isoforms, we reveal a novel role for pancortins in migration into the cortical plate. Interestingly, we observe opposing roles for alternate pancortin isoforms, with AMY overexpression and BMZ knock down both preventing proper migration of neuronal precursor cells. Finally, we show that BMZ can partially rescue a loss of APP expression and that APP can rescue effects of AMY overexpression, suggesting that pancortins act in conjunction with APP to regulate entry into the cortical plate. Taken together, these results suggest a biochemical and functional interaction between APP and pancortins, and reveal a previously unidentified role for pancortins in mammalian cortical development.
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Movimiento Celular/fisiología , Proteínas de la Matriz Extracelular/metabolismo , Glicoproteínas/metabolismo , Isoformas de Proteínas/metabolismo , Animales , Western Blotting , Línea Celular , Movimiento Celular/genética , Corteza Cerebral/metabolismo , Electroporación , Proteínas de la Matriz Extracelular/genética , Glicoproteínas/genética , Humanos , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Isoformas de Proteínas/genética , RatasRESUMEN
Adverse maternal and infant health outcomes among African Americans are increasingly recognized as indicators of a critical public health crisis in the United States. Research has found that stress is related to structural racism and the social determinants of health (SDOH) that cause avoidable, unfair inequities in resources, education, power, and opportunities across ethnic groups. This paper describes the SDOH needs and experiences of pregnant Black women from the perspective of doulas and Birthing Beautiful Communities (BBC) clients. The design was a qualitative description, using data collected over time (2017-2018, 2020-2021, and 2023). This study took place in Cleveland and Akron, Ohio and the sample included 58 clients, 26 doulas, and 2 resource intake specialist assistants (RISAs). Qualitative data included individual client interviews, three doula focus groups, and one interview with two BBC RISAs. Three coders used content analysis to deductively identify SDOHs and calculate the number of interviews that contained information about specific SDOHs. Although the sample reported issues with all SDOH, particular ones caused a cascade of SDOH effects. Transportation issues, for example, impeded women from being able to make it to work, doctor's appointments, and to purchase essential baby items (e.g., food, infant supplies). An inability to work-whether because of transportation challenges or pregnancy-related health complications-led to unstable housing and an inability to deal with transportation challenges. Many clients mentioned that housing was a major issue, with many clients experiencing housing instability. Implications include ensuring SDOH information is collected from a trusted source who can advocate and ensure access to a wide range of local resources, ensuring policies protect pregnant women from experiencing a cascade of SDOH that may contribute to continuing health disparate infant and maternal health outcomes in African American women.
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Negro o Afroamericano , Doulas , Grupos Focales , Investigación Cualitativa , Determinantes Sociales de la Salud , Humanos , Femenino , Embarazo , Ohio , Adulto , Negro o Afroamericano/estadística & datos numéricos , Negro o Afroamericano/psicología , Atención PerinatalRESUMEN
Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.
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Fertilidad , Flavonoles , Quercetina , Senoterapéuticos , Animales , Masculino , Ratones , Fertilidad/efectos de los fármacos , Quercetina/farmacología , Senoterapéuticos/farmacología , Flavonoles/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Senescencia Celular/efectos de los fármacos , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Hígado Graso/patología , Dieta Occidental/efectos adversos , Progresión de la Enfermedad , Deficiencia de Colina/complicaciones , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Despite intense interest in the proteolysis of the ß-Amyloid Precursor Protein (APP) in Alzheimer's disease, how the normal processing of this type I receptor-like glycoprotein is physiologically regulated remains ill-defined. In recent years, several candidate protein ligands for APP, including F-spondin, Reelin, ß1 Integrin, Contactins, Lingo-1, and Pancortin, have been reported. However, a cognate ligand for APP that regulates its processing by α- or ß-secretase has yet to be widely confirmed in multiple laboratories. Here, we developed new assays in an effort to confirm a role for one or more of these candidate ligands in regulating APP ectodomain shedding in a biologically relevant context. A comprehensive quantification of APPsα and APPsß, the immediate products of secretase processing, in both non-neuronal cell lines and primary neuronal cultures expressing endogenous APP yielded no evidence that any of these published candidate ligands stimulate ectodomain shedding. Rather, Reelin, Lingo-1, and Pancortin-1 emerged as the most consistent ligands for significantly inhibiting ectodomain shedding. These findings led us to conduct further detailed analyses of the interactions of Reelin and Lingo-1 with APP.
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Precursor de Proteína beta-Amiloide/metabolismo , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Células Cultivadas , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Ligandos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteína Reelina , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome trafficking/turnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.
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Antígenos CD , Proteínas de la Membrana , Neoplasias , Animales , Humanos , Masculino , Ratones , Inmunoglobulinas/genética , Melanoma , Proteínas de la Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias de la Próstata , Tetraspaninas/genética , Microambiente Tumoral , Antígenos CD/metabolismoRESUMEN
The greatest risk factor for cognitive decline is aging. The biological mechanisms for this decline remain enigmatic due, in part, to the confounding of normal aging mechanisms and those that contribute to cognitive impairment. Importantly, many individuals exhibit impaired cognition in age, while some retain functionality despite their age. Here, we establish a behavioral testing paradigm to characterize age-related cognitive heterogeneity in inbred aged C57BL/6 mice and reliably separate animals into cognitively "intact" (resilient) and "impaired" subgroups using a high-resolution home-cage testing paradigm for spatial discrimination. RNA sequencing and subsequent pathway analyses of cognitively stratified mice revealed molecular signatures unique to cognitively impaired animals, including transcriptional down-regulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) and sirtuin (Sirt1 and Sirt3) expression in the hippocampus. Mitochondrial function assessed using high-resolution respirometry indicated a reduced OXPHOS coupling efficiency in cognitively impaired animals with subsequent hippocampal analyses revealing an increase in the oxidative damage marker (3-nitrotyrosine) and an up-regulation of antioxidant enzymes (Sod2, Sod1, Prdx6, etc.). Aged-impaired animals also showed increased levels of IL-6 and TNF-α gene expression in the hippocampus and increased serum levels of proinflammatory cytokines, including IL-6. These results provide critical insight into the diversity of brain aging in inbred animals and reveal the unique mechanisms that separate cognitive resilience from cognitive impairment. Our data indicate the importance of cognitive stratification of aging animals to delineate the mechanisms underlying cognitive impairment and test the efficacy of therapeutic interventions.
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Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H2S supplementation or by re-expressing CBS. Conversely, the CBS/H2S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H2S supplementation. Here we reveal that in the aging brain, the CBS/H2S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H2S axis in astrocytes that may be disrupted in the aged brain.
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Envejecimiento , Astrocitos , Encéfalo , Cistationina betasintasa , Anciano , Animales , Humanos , Ratones , Envejecimiento/metabolismo , Envejecimiento/patología , Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Cistationina/metabolismo , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/metabolismoRESUMEN
Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m , H2-D1 , H2-K1 , H2-M3 , H2-Q6 , and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A , suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
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Skeletal muscle has a central role in maintaining metabolic homeostasis. 17α-estradiol (17α-E2), a naturally-occurring non-feminizing diastereomer of 17ß-estradiol that demonstrates efficacy for improving metabolic outcomes in male, but not female, mice. Despite several lines of evidence showing that 17α-E2 treatment improves metabolic parameters in middle-aged obese and old male mice through effects in brain, liver, and white adipose tissue little is known about how 17α-E2 alters skeletal muscle metabolism, and what role this may play in mitigating metabolic declines. Therefore, this study aimed to determine if 17α-E2 treatment improves metabolic outcomes in skeletal muscle from obese male and female mice following chronic high fat diet (HFD) administration. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during HFD. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and reduced the abundance of most of the proteins related to lipolysis and beta-oxidation. In contrast to males, 17α-E2 treatment in female mice had little effect on the DAGs and ceramides content, muscle inflammatory cytokine levels, or changes to the relative abundance of proteins involved in beta-oxidation. These data support to the growing evidence that 17α-E2 treatment could be beneficial for overall metabolic health in male mammals.
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Major histocompatibility complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses, but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here, we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating ribosome affinity purification-qPCR analysis of 3-6- and 18-22-month-old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I-binding leukocyte immunoglobulin-like (Lilrs) and paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell -autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
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Enfermedad de Alzheimer , Microglía , Humanos , Ratones , Ratas , Animales , Microglía/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Complejo Mayor de Histocompatibilidad , Envejecimiento/fisiología , Encéfalo/metabolismoRESUMEN
Emerging evidence suggests that patients with Alzheimer's disease (AD) may show accelerated sarcopenia phenotypes. To investigate whether pathological changes associated with neuronal death and cognitive dysfunction also occur in peripheral motor neurons and muscle as a function of age, we used the triple transgenic mouse model of AD (3xTgAD mice) that carries transgenes for mutant forms of APP, Tau, and presenilin proteins that are associated with AD pathology. We measured changes in motor neurons and skeletal muscle function and metabolism in young (2 to 4 month) female control and 3xTgAD mice and in older (18-20 month) control and 3xTgAD female mice. In older 3xTgAD mice, we observed a number of sarcopenia-related phenotypes, including significantly fragmented and denervated neuromuscular junctions (NMJs) associated with a 17% reduction in sciatic nerve induced vs. direct muscle stimulation induced contractile force production, and a 30% decrease in gastrocnemius muscle mass. On the contrary, none of these outcomes were found in young 3xTgAD mice. We also measured an accumulation of amyloid-ß (Aß) in both skeletal muscle and neuronal tissue in old 3xTgAD mice that may potentially contribute to muscle atrophy and NMJ disruption in the older 3xTgAD mice. Furthermore, the TGF-ß mediated atrophy signaling pathway is activated in old 3xTgAD mice and is a potential contributing factor in the muscle atrophy that occurs in this group. Perhaps surprisingly, mitochondrial oxygen consumption and reactive oxygen species (ROS) production are not elevated in skeletal muscle from old 3xTgAD mice. Together, these results provide new insights into the effect of AD pathological mechanisms on peripheral changes in skeletal muscle.
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When recalling autobiographical memories, individuals often experience visual images associated with the event. These images can be constructed from two different perspectives: first person, in which the event is visualized from the viewpoint experienced at encoding, or third person, in which the event is visualized from an external vantage point. Using a novel technique to measure visual perspective, we examined where the external vantage point is situated in third-person images. Individuals in two studies were asked to recall either 10 or 15 events from their lives and describe the perspectives they experienced. Wide variation in spatial locations was observed within third-person perspectives, with the location of these perspectives relating to the event being recalled. Results suggest remembering from an external viewpoint may be more common than previous studies have demonstrated.
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Recuerdo Mental , Percepción Visual , Adolescente , Femenino , Humanos , Masculino , Memoria Episódica , Campos Visuales , Adulto JovenRESUMEN
This study describes findings of a phenomenological study of Black women's experiences with a community-based perinatal support organization based in Cleveland, Ohio. Twenty-five women participated in interviews after their babies were born about how the organization in general, and perinatal support professionals (PSPs) in particular supported them during their pregnancies and the meaning of that support. The overall meaning of perinatal support was described as easing participants' transitions into motherhood through reducing uncertainty, social isolation, and stress. The three main themes described the meaning of perinatal support and included (a) easing the transition to motherhood through emotional support, expressed via love and help managing relationships; (b) easing the transition to motherhood through instrumental support, expressed via helping with basic needs and obtaining material goods for the baby; and (c) easing the transition to motherhood through informational support, expressed via help navigating systems and information, and gaining knowledge and skills around mothering and self-care. Implications for practice, policy, and research are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Asunto(s)
Negro o Afroamericano , Madres , Femenino , Humanos , Ohio , Embarazo , Investigación Cualitativa , Apoyo SocialRESUMEN
The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.