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The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells in the mouse cerebellum (both sexes). In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to threefold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief input stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location.
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Ratones Endogámicos C57BL , Células de Purkinje , Transmisión Sináptica , Animales , Células de Purkinje/fisiología , Ratones , Transmisión Sináptica/fisiología , Masculino , Femenino , Cerebelo/fisiología , Cerebelo/citología , Potenciales Postsinápticos Excitadores/fisiología , Sinapsis/fisiología , Factores de Tiempo , Potenciales de Acción/fisiologíaRESUMEN
During the perioperative period of transplantation, patients experience hypotension secondary to the side effects of anesthesia, surgical stress, inflammatory triggering, and intraoperative fluid shifts, among others causes. Vasopressor support, in this context, must reverse systemic hypotension, but ideally, the agents used should benefit allograft function and avoid the adverse events commonly seen after transplantation. Traditional therapies to reverse hypotension include catecholamine vasopressors (norepinephrine, epinephrine, dopamine, and phenylephrine), but their utility is limited when considering allograft complications and adverse events such as arrhythmias with agents with beta-adrenergic properties. Synthetic angiotensin II (AT2S-[Giapreza]) is a novel vasopressor indicated for distributive shock with a unique mechanism of action as an angiotensin receptor agonist restoring balance to an often-disrupted renin angiotensin aldosterone system. Additionally, AT2S provides a balanced afferent and efferent arteriole vasoconstriction at the level of the kidney and could avoid the arrhythmic complications of a beta-adrenergic agonist. While the data, to date, are limited, AT2S has demonstrated safety in case reports, pilot studies, and small series in the kidney, liver, heart, and lung transplant populations. There are physiologic and hemodynamic reasons why AT2S could be a more utilized agent in these populations, but further investigation is warranted.
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PURPOSE/BACKGROUND: People who smoke cigarettes and drink alcohol heavily are less likely to quit smoking compared with those who do not drink heavily. The current study examined the effects of a 12-week treatment phase of combination varenicline and nicotine patch compared with placebo and nicotine patch on smoking cessation (primary outcome) and alcohol consumption (secondary outcome) in heavy drinking smokers at 26-week follow-up. METHODS/PROCEDURES: Participants were daily smokers who met heavy drinking criteria. They were randomly assigned to receive either varenicline and nicotine patch (n = 61) or placebo and nicotine patch (n = 61) for 12 weeks. At week 26, self-reports of point prevalence cigarette abstinence were biochemically confirmed, and past-month alcohol drinking days and heavy drinking days were assessed. FINDINGS/RESULTS: At week 26, smoking quit rates did not differ by treatment group (25% varenicline and 26% placebo). Relative to week 12 outcomes, week 26 quit rates significantly dropped off in the varenicline group but not in the placebo group. Alcohol drinking reductions for the whole sample that were previously observed from baseline to week 12 were sustained at week 26, although they did not differ between treatment groups. IMPLICATIONS/CONCLUSIONS: In heavy drinking smokers, smoking cessation success was evident in a quarter of the total sample at 3 months postmedication discontinuation. At this time, quit rates were the same between those who received varenicline and nicotine patch and those who received nicotine patch alone. Future research is warranted to examine what may aid in longer-term smoking quit rates in heavy drinking smokers.
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Consumo de Bebidas Alcohólicas , Agentes para el Cese del Hábito de Fumar , Cese del Hábito de Fumar , Dispositivos para Dejar de Fumar Tabaco , Vareniclina , Humanos , Vareniclina/administración & dosificación , Vareniclina/farmacología , Cese del Hábito de Fumar/métodos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios de Seguimiento , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Quimioterapia Combinada , Resultado del Tratamiento , Agonistas Nicotínicos/administración & dosificación , Método Doble CiegoRESUMEN
Injury responses in terminally differentiated cells such as neurons is tightly regulated by pathways aiding homeostatic maintenance. Cancer patients subjected to neuronal injury in brain radiation experience cognitive declines similar to those seen in primary neurodegenerative diseases. Numerous studies have investigated the effect of radiation in proliferating cells of the brain, yet the impact in differentiated, post-mitotic neurons, especially the structural and functional alterations remain largely elusive. We identified that microtubule-associated tau is a critical player in neuronal injury response via compartmentalized functions in both repair-centric and synaptic regulatory pathways. Ionizing radiation-induced injury acutely induces increase in phosphorylated tau in the nucleus and directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX after irradiation, indicating that tau may play an important role in neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels after irradiation, the latter being a positive regulator of protein translation. This cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Consequently, novel object recognition test showed decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity showed increase in delta and theta band oscillations, often seen in dementia patients. Our findings demonstrate tau's previously undefined, multifunctional role in acute responses to injury, ranging from DDR response in the nucleus to synaptic function within a neuron. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.
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Background: The most prevalent cancer treatments cause cell death through DNA damage. However, DNA damage response (DDR) repair pathways, initiated by tumor cells, can withstand the effects of anticancer drugs, providing justification for combining DDR inhibitors with DNA-damaging anticancer treatments. Methods: Cell viability assays were performed with CellTiter-Glo assay. DNA damage was evaluated using Western blotting analysis. RNA-seq and single-cell level expression were used to identify the DDR signatures. In vivo, studies were conducted in mice to determine the effect of ATris on TMZ sensitization. Results: We found a subpopulation of glioma sphere-forming cells (GSCs) with substantial synergism with temozolomide (TMZ) using a panel of 3 clinical-grade ataxia-telangiectasia- and Rad3-related kinase inhibitors (ATRis), (elimusertib, berzosertib, and ceralasertib). Interestingly, most synergistic cell lines had O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, indicating that ATRi mainly benefits tumors with no MGMT repair. Further, TMZ activated the ATR-checkpoint kinase 1 (Chk1) axis in an MGMT-dependent way. TMZ caused ATR-dependent Chk1 phosphorylation and DNA double-strand breaks as shown by increased γH2AX. Increased DNA damage and decreased Chk1 phosphorylation were observed upon the addition of ATRis to TMZ in MGMT-methylated (MGMT-) GSCs. TMZ also improved sensitivity to ATRis in vivo, as shown by increased mouse survival with the TMZ and ATRi combination treatment. Conclusions: This research provides a rationale for selectively targeting MGMT-methylated cells using ATRis and TMZ combination. Overall, we believe that MGMT methylation status in GBM could serve as a robust biomarker for patient selection for ATRi combined with TMZ.
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BACKGROUND: Hypoperfusion leads to allograft injury during kidney transplantation. Catecholamine vasopressors are used to maintain blood pressure in the perioperative period but have demonstrated negative outcomes in the deceased-donor kidney transplant population. Little is known regarding living donor kidney transplants (LDKTs) and vasopressor use. The aim of this study is to describe the incidence of vasopressor use in LDKT and characterize its effects on allograft function and patient outcomes. METHODS: This retrospective, observational cohort study included adult patients who underwent an isolated LDKT between August 1, 2017, and September 1, 2018. Patients were divided into those who received perioperative vasopressors and those who did not. The primary objective was to compare allograft function between LDKT recipients that received vasopressors and those who did not. Secondary outcomes included safety endpoints and the identification of clinical variables associated with vasopressor use. RESULTS: A total of 67 patients received an LDKT during the study period. Of those, 25 (37%) received perioperative vasopressors, and 42 (62%) did not. Poor graft function, as defined by the development of slow or delayed graft function, occurred more frequently in patients receiving perioperative vasopressors compared with those who did not (6 [24%] vs 1 [2.4%], P = .016). In multivariable regression modeling, only perioperative vasopressors were statistically significantly associated with poor graft function. In addition, patients exposed to vasopressors experienced more postoperative arrhythmias (8 [32%] vs 1 [4.8%], P = .0025). CONCLUSION: Using perioperative vasopressors was independently associated with worsened early renal allograft function, including delayed graft function and adverse events in the LDKT population.
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Trasplante de Riñón , Adulto , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Donadores Vivos , Funcionamiento Retardado del Injerto/etiología , Supervivencia de Injerto , Aloinjertos , Receptores de TrasplantesRESUMEN
Objectives: The current study sought to qualitatively characterize the experiences of American users in a recent open trial of the Horyzons digital platform. Methods: In total, 20 users on Horyzons USA completed semistructured interviews 12 weeks after their orientation to the platform and addressed questions related to (1) the platform, (2) their online therapist, and (3) the peer workers and community space. A hybrid inductive-deductive coding strategy was used to conduct a thematic analysis of the data (NCT04673851). Results: The authors identified seven prominent themes that mapped onto the three components of self-determination theory. Features of the platform itself as well as inter- and intra-personal factors supported the autonomous use of Horyzons. Users also reflected that their perceived competence in social settings and in managing mental health was increased by the familiarity, privacy, and perceived safety of the platform and an emphasis on personalized therapeutic content. The behaviors or traits of online therapists as perceived by users and regular contact with peers and peer support specialists satisfied users' need for relatedness and promoted confidence in social settings. Users also described aspects of Horyzons USA that challenged their satisfaction of autonomy, competence, and relatedness, highlighting potential areas for future iterations of the platform's content and interface. Conclusions: Horyzons USA is a promising digital tool that provides young adults with psychosis with the means to access tailored therapy material on demand and a supportive digital community to aid in the recovery process.
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The naive detection of scheduled H drug oxytocin is a vital requisite, owing to its deleterious impact on societal affluence prompted by unconstrained usage. Therefore, a reliable, cost-effective, and quick-to-respond analytic technique for this drug is in ample demand. In this work, we report electrochemical detection of oxytocin employing novel nitrogen, phosphorus co-doped coke-derived graphene (NPG) modified electrode. The electro-oxidation behavior of oxytocin was investigated on the NPG modified electrode by square wave stripping voltammetry (SWSV) in 0.1 M phosphate buffer of pH 7. The oxidation peak current was linear in two ranges, spanning from 0.1 nM to 10 nM and 15 nM to 95 nM. The limit of detection at the NPG electrode was calculated to be 40 pM. The practical application of developed sensor for the determination of oxytocin was examined in edible products and body fluids, hence signifying the possibility of having real-time surveillance over its misusage.
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Coque , Grafito , Técnicas Electroquímicas/métodos , Electrodos , Límite de Detección , Nitrógeno , Oxitocina , Fosfatos , FósforoRESUMEN
Although onion-like carbon nanostructures (OLCs) are attractive materials for energy storage, their commercialization is hampered by the absence of a simple, cost-effective, large-scale synthesis route and binder-free electrode processing. The present study employs a scalable and straightforward technique to fabricate sonochemically tailored OLCs-based high-performance supercapacitor electrode material. An enhanced supercapacitive performance was demonstrated by the OLCs when sonicated in DMF at 60 °C for 15 min, with a specific capacitance of 647 F/g, capacitance retention of 97% for 5000 cycles, and a charge transfer resistance of 3 Ω. Furthermore, the OLCs were employed in the electrochemical quantification of methylene blue, a potential COVID-19 drug. The sensor demonstrated excellent analytical characteristics, including a linear range of 100 pM to 1000 pM, an ultralow sensitivity of 64.23 pM, and a high selectivity. When used to identify and quantify methylene blue in its pharmaceutical formulation, the sensor demonstrated excellent reproducibility, high stability, and satisfactory recovery.
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Nuclear movement is a fundamental process of eukaryotic cell biology. Skeletal muscle presents an intriguing model to study nuclear movement because its development requires the precise positioning of multiple nuclei within a single cytoplasm. Furthermore, there is a high correlation between aberrant nuclear positioning and poor muscle function. Although many genes that regulate nuclear movement have been identified, the mechanisms by which these genes act are not known. Using Drosophila melanogaster muscle development as a model system and a combination of live-embryo microscopy and laser ablation of nuclei, we have found that clustered nuclei encompass at least two phenotypes that are caused by distinct mechanisms. Specifically, Ensconsin is necessary for productive force production to drive any movement of nuclei, whereas Bocksbeutel and Klarsicht are necessary to form distinct populations of nuclei that move to different cellular locations. Mechanistically, Ensconsin regulates the number of growing microtubules that are used to move nuclei, whereas Bocksbeutel and Klarsicht regulate interactions between nuclei.
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Proteínas Asociadas a Microtúbulos/metabolismo , Centro Organizador de los Microtúbulos/metabolismo , Músculo Esquelético/metabolismo , Animales , Transporte Biológico , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Cinesinas , Proteínas de Microtúbulos/metabolismo , Proteínas Asociadas a Microtúbulos/fisiología , Microtúbulos/metabolismo , Membrana Nuclear/metabolismoRESUMEN
Recent studies have demonstrated that selective activation of mammalian target of rapamycin complex 1 (mTORC1) in the cerebellum by deletion of the mTORC1 upstream repressors TSC1 or phosphatase and tensin homolog (PTEN) in Purkinje cells (PCs) causes autism-like features and cognitive deficits. However, the molecular mechanisms by which overactivated mTORC1 in the cerebellum engenders these behaviors remain unknown. The eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) is a central translational repressor downstream of mTORC1. Here, we show that mice with selective ablation of 4E-BP2 in PCs display a reduced number of PCs, increased regularity of PC action potential firing, and deficits in motor learning. Surprisingly, although spatial memory is impaired in these mice, they exhibit normal social interaction and show no deficits in repetitive behavior. Our data suggest that, downstream of mTORC1/4E-BP2, there are distinct cerebellar mechanisms independently controlling social behavior and memory formation.
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Trastorno Autístico/genética , Proteínas Portadoras/metabolismo , Factores Eucarióticos de Iniciación/metabolismo , Biosíntesis de Proteínas/genética , Células de Purkinje/metabolismo , Memoria Espacial/fisiología , Animales , Humanos , RatonesRESUMEN
APOE4 is a major genetic risk factor for Alzheimer's disease and high amyloid-ß (Aß) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific APOE-modulated Aß-dependent and Aß-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of APOE in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate. We have previously demonstrated that systemic epidermal growth factor (EGF) treatment, which is important for vascular function, at early stages of pathology (treatment from 6 to 8 months) is beneficial for recognition and spatial memory and cerebrovascular function in female mice that express APOE4. These data raise the important question of whether EGF can improve APOE4-associated cerebrovascular and behavioral dysfunction when treatment is initiated at an age of advanced pathology. Positive findings would support the development of therapies that target cerebrovascular dysfunction associated with APOE4 in aging and AD in individuals with advanced cognitive impairment. Therefore, in this study female mice that express APOE4 in the absence (E4FAD- mice) or presence (E4FAD+ mice) of Aß overproduction were treated from 8 to 10 months of age systemically with EGF. EGF treatment mitigated behavioral dysfunction in recognition memory and spatial learning and improved hippocampal neuronal function in both E4FAD+ and E4FAD- mice, suggesting that EGF treatment improves Aß-independent APOE4-associated deficits. The beneficial effects of EGF treatment on behavior occurred in tandem with improved markers of cerebrovascular function, including lower levels of fibrinogen, lower permeability when assessed by MRI and higher percent area coverage of laminin and CD31 in the hippocampus. These data suggest a mechanistic link among EGF signaling, cerebrovascular function and APOE4-associated behavioral deficits in mice with advanced AD-relevant pathology.
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Three months of exercise training (ET) decreases soluble Aß40 and Aß42 levels in an intensity dependent manner early in life in Tg2576 mice (Moore et al., 2016). Here, we examined the effects of 12 months of low- and high- intensity exercise training on cognitive function and amyloid plaque load in the cortex and hippocampus of 15-month-old Tg2576 mice. Low- (LOW) and high- (HI) intensity ET animals ran at speeds of 15 m/min on a level treadmill and 32 m/min at a 10% grade, respectively, for 60 min/day, five days/week, from 3 to 15 months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. ET mice demonstrated a significantly lower amyloid plaque load in the cortex and hippocampus that was intensity dependent. Improvement in cognitive function, assessed by Morris Water Maze and Novel Object Recognition tests, was greater in the HI group compared to the LOW and SED groups. LOW mice performed better in the initial latency to the platform location during the probe trial of the Morris Water Maze (MWM) test than SED, but not in any other aspect of MWM or the Novel Object Recognition test. The results of this study indicate that exercise training decreases amyloid plaque load in an intensity dependent manner and that high-intensity exercise training improves cognitive function relative to SED mice, but the intensity of the LOW group was below the threshold to demonstrate robust improvement in cognitive function in Tg2576 mice.
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Arterial spin labeling (ASL) MRI, based on endogenous contrast from blood water, is used in research and diagnosis of cerebral vascular conditions. However, artifacts due to imperfect imaging conditions such as B0-inhomogeneity (ΔB0) could lead to variations in the quantification of relative cerebral blood flow (CBF). In this study, we evaluate a new approach using tagging distance dependent Z-spectrum (TADDZ) data, similar to the ΔB0 corrections in the chemical exchange saturation transfer (CEST) experiments, to remove the imaging plane B0 inhomogeneity induced CBF artifacts in ASL MRI. Our results indicate that imaging-plane B0-inhomogeneity can lead to variations and errors in the relative CBF maps especially under small tagging distances. Along with an acquired B0 map, TADDZ data helps to eliminate B0-inhomogeneity induced artifacts in the resulting relative CBF maps. We demonstrated the effective use of TADDZ data to reduce variation while subjected to systematic changes in ΔB0. In addition, TADDZ corrected ASL MRI, with improved consistency, was shown to outperform conventional ASL MRI by differentiating the subtle CBF difference in Alzheimer's disease (AD) mice brains with different APOE genotypes.
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Circulación Cerebrovascular , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Enfermedad de Alzheimer/diagnóstico por imagen , Animales , Artefactos , Modelos Animales de Enfermedad , Genotipo , Procesamiento de Imagen Asistido por Computador , Masculino , Ratones , Ratones Noqueados para ApoE , Perfusión , Marcadores de SpinRESUMEN
Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Lisofosfatidilcolinas/administración & dosificación , Memoria/efectos de los fármacos , Animales , Ácido Ascórbico/análogos & derivados , Química Encefálica , Ratones , Aprendizaje Espacial/efectos de los fármacosRESUMEN
Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer's disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 ( APOE4), Amyloid-ß (Aß), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aß, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aß42 via expression of 5 Familial Alzheimer's disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/-/ APOE+/+ (EFAD+)] and noncarriers [5xFAD-/-/ APOE+/+ (EFAD-)] to compare the effects of peripheral inflammation in the presence or absence of human Aß overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aß deposition. Thus, APOE4, Aß, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.
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Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Trastornos Cerebrovasculares/metabolismo , Disfunción Cognitiva/metabolismo , Inflamación/metabolismo , Péptidos beta-Amiloides/genética , Animales , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Permeabilidad Capilar/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Trastornos Cerebrovasculares/patología , Disfunción Cognitiva/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Escherichia coli , Humanos , Inflamación/patología , Lipopolisacáridos , Masculino , Ratones Transgénicos , Distribución Aleatoria , Reconocimiento en Psicología/fisiologíaRESUMEN
Blood-brain barrier (BBB) coverage plays a central role in the homeostasis of the central nervous system (CNS). The BBB is dynamically maintained by astrocytes, pericytes and brain endothelial cells (BECs). Here, we detail methods to assess BBB coverage using single cultures of immortalized human BECs, single cultures of primary mouse BECs, and a humanized triple culture model (BECs, astrocytes and pericytes) of the BBB. To highlight the applicability of the assays to disease states, we describe the effect of oligomeric amyloid-ß (oAß), which is an important contributor to Alzheimer's disease (AD) progression, on BBB coverage. Further, we utilize the epidermal growth factor (EGF) to illuminate the drug screening potential of the techniques. Our results show that single and triple cultured BECs form meshwork-like structures under basal conditions, and that oAß disrupts this cell meshwork formation and degenerates the preformed mesh structures, but EGF blocks this disruption. Thus, the techniques described are important for dissecting fundamental and disease-relevant processes that modulate BBB coverage.
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Barrera Hematoencefálica/citología , Barrera Hematoencefálica/patología , Capilares/citología , Capilares/patología , Técnicas de Cultivo de Célula/métodos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/farmacología , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitos/patología , Barrera Hematoencefálica/efectos de los fármacos , Capilares/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Factor de Crecimiento Epidérmico/farmacología , Humanos , Ratones , Pericitos/citología , Pericitos/efectos de los fármacos , Pericitos/patologíaRESUMEN
Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer's disease (AD). Two important risk factors for cerebrovascular dysfunction are APOE and female sex, which are primarily researched in the context of high amyloid-ß (Aß) levels as found in AD. However, APOE4 and sex modulate Aß-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Aß-independent models that incorporate APOE4 and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express APOE4 and overproduce Aß, without affecting Aß levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Aß-independent cerebrovascular dysfunction. In eight-month old mice that express human APOE, the interaction of APOE4 and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4. Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk.
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Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h-APOE rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-ß (Aß) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits. EFAD mice were designed as a temporally useful preclinical FAD-Tg-mouse model expressing the h-APOE genotypes for identifying mechanisms underlying APOE-modulated symptoms of AD pathology. From their first description in 2012, EFAD mice have enabled critical basic and therapeutic research. Here we review insights gleaned from the EFAD mice and summarize future directions.
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Enfermedad de Alzheimer , Apolipoproteína E4/genética , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Animales , Apolipoproteína E4/sangre , Humanos , Ratones , Ratones Transgénicos , FenotipoRESUMEN
Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer's disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aß)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aß levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aß42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 µg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aß levels. Collectively, these data suggest that EGF can prevent Aß-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.