APOE AS A METABOLIC REGULATOR IN HUMANS, MICE, AND ASTROCYTES

Altered metabolic pathways appear to play central roles in the pathophysiology of late-onset Alzheimer’s disease (AD). Carrier status of the E4 allele of the APOE gene is the strongest genetic risk factor for late-onset AD, and increasing evidence suggests that E4 carriers may be at an increased risk for neurodegeneration based on inherent metabolic impairments. A new appreciation is forming for the role of APOE in cerebral metabolism, and how nutritional factors may impact this role. In chapter 1, the literature on nutritional interventions in E4 carriers aimed at mitigating disease risk is reviewed. Studies investigating the mechanism by which E4 increases disease risk have focused primarily on the association of E4 with the neuropathological hallmarks. While these studies have aided in our understanding of the role of E4 in late-disease pathology, investigating metabolic signatures of E4 carriers who have not yet developed neuropathology gives insight into the potential earlier mechanisms of E4 as a risk factor for AD. For example, an early and consistent biological hallmark of AD is cerebral glucose hypometabolism as observed by fluorodeoxyglucose positron emission tomography (FDG-PET). Interestingly, E4 carriers also display an AD-like pattern of decreased glucose metabolism by FDG-PET far before clinical symptomology. Since glucose hypometabolism occurs early in AD and early in E4 carriers, it may represent a critical prodromal phase of AD. Beyond this brain imaging finding, it is unclear if APOE has any other discernable metabolic effects in cognitively unimpaired young people. In chapter 2 we bridge this knowledge gap in the field. We utilized indirect calorimetry (IC) as a method for assessing metabolism in young and middle aged volunteers with and without the E4 allele. While IC is commonly used in clinical settings to assess nutritional status, it has never been used to assess risk for cognitive decline. Thus, repurposing IC to study the metabolic effects of an AD risk factor such as E4 represents a simple, cost-effective, and innovative new approach. We found that young female E4 carriers show a lower resting energy expenditure compared to non-carriers. We also tested how E4 carriage affects response to a glucose challenge by administering a glucose rich beverage in conjunction with IC measurements and plasma metabolomics. We found that female E4 carriers were unable to increase oxygen consumption relative to non-carriers, reflecting an impairment in glucose oxidation. Additionally, the plasma metabolome of E4 carriers showed increased lactate and an overall metabolic profile consistent with aerobic glycolysis. We translated these findings to mice expressing the human alleles of APOE. We found that E4 mice on a normal chow diet have lower energy expenditure than E3 mice, a difference further exacerbated by high carbohydrate diet feeding. Stable isotope tracing in mice whole brains and astrocytes implicate increased utilization of aerobic glycolysis as a mechanism for altered glucose handling in E4 carriers. Another pathological feature of the Alzheimer’s brain is glial lipid accumulation. The mechanism for this is largely unknown. In chapter 3, the literature pertaining to lipid droplets (LD) in the brain is reviewed. We show that LDs are much more than simple fat depots, playing critical roles in metabolism, inflammation, and various neurodegenerative diseases. In chapter 4, the effect of the E4 allele on astrocyte LD accumulation and turnover is assessed. Using an in vitro model of APOE we probed the storage and oxidation capacity of fatty acids in E3 and E4 astrocytes. We observed that E4 astrocytes exhibit greater storage of fatty acids as LDs under control and lipid loaded conditions compared to E3 astrocytes. Furthermore, we found that E4 astrocytes rely on these LDs as a source of fuel for oxidation. Therefore, APOE appears to regulate whole body energy expenditure, cerebral glucose oxidation, astrocyte LD metabolism, and risk for a host of metabolic diseases. In chapter 5, the evolutionary history of APOE is presented to posit a hypothesis for why E4 may be disadvantageous in modern times compared to its prior advantages in the pre-historic era. These results point toward a larger role for APOE in the regulation of metabolism than previously understood and advocates for alternative nutritional approaches including calorie reduction and intermittent fasting as plausible interventions to mitigate disease risk in E4 carriers

\u3cem\u3eAPOE\u3c/em\u3e and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In the current mini-review article, we summarize the known effects of APOE on cerebral metabolism and cerebrovascular function, with a special emphasis on recent findings via neuroimaging approaches

Endothelin-1 Promotes Bovine Corneal Endothelial Cell Proliferation via a MAPK Pathway: Implications for Keratopathy and Deturgescence

The corneal endothelium is vital in maintaining the functions of the cornea, namely hydration, thickness, and transparency. Diseases that impair the corneal endothelium are currently remedied solely via surgery. These surgeries present obstacles to patients of underserved areas due to cost, ineffectiveness, and lack of access. Trachoma, an infection which can cause corneal opacities, is the leading cause of infectious blindness in the world. In order to eradicate trachoma, epidemiological data is needed. Three villages in Kasigau, Kenya were studied to quantify the occurrence of trachoma in the region. The three villages were found to have adequate access to antibiotics and an unremarkable incidence of trachoma symptoms. An alternative therapy to surgery for corneal endothelial disease is needed. Endothelin-1 (ET-1) has been shown to induce cell proliferation in bovine corneal endothelial cells (BCEC). The pathway by which this occurs is not well understood. It was hypothesized that ET-1 induces proliferation through the mitogen-activated protein kinase (MAPK) pathway. Treatment of BCEC with 10 nM ET-1 for 15 min induced a 4.3 fold increase in pERK1/2 (p \u3c 0.001). Furthermore, 30 min pre-treatment with a MAPK pathway inhibitor before ET-1 treatment significantly decreased pERK1/2 expression (p\u3c0.05). These results suggest that the MAPK pathway may be involved in BCEC ET-1 induced proliferation

APOΕ4 Lowers Energy Expenditure in Females and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer\u27s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a \u27Warburg like\u27 endophenotype that is observable in young females decades prior to clinically manifest AD

A typology of practice narratives during the implementation of a preventive, community intervention trial

<p>Abstract</p> <p>Background</p> <p>Traditional methods of process evaluation encompass what components were delivered, but rarely uncover how practitioners position themselves and act relative to an intervention being tested. This could be crucial for expanding our understanding of implementation and its contribution to intervention effectiveness.</p> <p>Methods</p> <p>We undertook a narrative analysis of in-depth, unstructured field diaries kept by nine community development practitioners for two years. The practitioners were responsible for implementing a multi-component, preventive, community-level intervention for mothers of new babies in eight communities, as part of a cluster randomised community intervention trial. We constructed a narrative typology of approaches to practice, drawing on the phenomenology of Alfred Schutz and Max Weber's Ideal Type theory.</p> <p>Results</p> <p>Five types of practice emerged, from a highly 'technology-based' type that was faithful to intervention specifications, through to a 'romantic' type that held relationships to be central to daily operations, with intact relationships being the final arbiter of intervention success. The five types also differed in terms of how others involved in the intervention were characterized, the narrative form (<it>e.g</it>., tragedy, satire) and where and how transformative change in communities was best created. This meant that different types traded-off or managed the priorities of the intervention differently, according to the deeply held values of their type.</p> <p>Conclusions</p> <p>The data set constructed for this analysis is unique. It revealed that practitioners not only exercise their agency within interventions, they do so systematically, that is, according to a pattern. The typology is the first of its kind and, if verified through replication, may have value for anticipating intervention dynamics and explaining implementation variation in community interventions.</p

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In the current mini-review article, we summarize the known effects of APOE on cerebral metabolism and cerebrovascular function, with a special emphasis on recent findings via neuroimaging approaches

4/11/26, chasse à courre chez la duchesse d'Uzès [à La Celle-lès-Bordes] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 114253Appartient à l’ensemble documentaire : Pho20RolImage de press

The Lightweight Integrated Solar Array and Transceiver (LISA-T): second generation advancements and the future of SmallSat power generation

This paper describes the second generation advancements of the Lightweight Integrated Solar Array and Transceiver (LISA-T) currently being developed at NASA’s Marshall Space Flight Center. LISA-T is a launch stowed, orbit deployed array on which thin-film photovoltaic and antenna elements are embedded. Inherently, small satellites are limited in surface area, volume, and mass allocation; driving competition between power, communications, and GN&C (guidance navigation and control) subsystems. This restricts payload capability and limits the value of these low-cost satellites. LISA-T is addressing this issue, deploying large-area arrays from a reduced volume and mass envelope – greatly enhancing power generation and communications capabilities of small spacecraft. A matrix of options are in development, including planar (pointed) and omnidirectional (non-pointed) arrays. The former is seeking the highest performance possible while the latter is seeking GN&C simplicity. In both cases, power generation ranges from tens of watts to several hundred with an expected specific power \u3e250W/kg and a stowed power density \u3e200kW/m3. Options for leveraging both high performance, ‘typical cost’ triple junction thin-film solar cells as well as moderate performance, low cost cells are being developed. Alongside, both UHF (ultra high frequency) and S-band antennas are being integrated into the array to move their space claim away from the spacecraft and open the door for omnidirectional communications and electronically steered phase arrays