Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents.

Visceral adiposity has been associated with altered microstructural properties of white matter in adolescents. Previous evidence suggests that circulating phospholipid PC(16:0/2:0) may mediate this association. To investigate the underlying biology, we performed a genome-wide association study (GWAS) of the shared variance of visceral fat, PC(16:0/2:0), and white matter microstructure in 872 adolescents from the Saguenay Youth Study. We further studied the metabolomic profile of the GWAS-lead variant in 931 adolescents. Visceral fat and white matter microstructure were assessed with magnetic resonance imaging. Circulating metabolites were quantified with serum lipidomics and metabolomics. We identified a genome-wide significant association near DHCR24 (Seladin-1) encoding a cholesterol-synthesizing enzyme (rs588709, p = 3.6 × 10-8); rs588709 was also associated nominally with each of the three traits (white matter microstructure: p = 2.1 × 10-6, PC(16:0/2:0): p = 0.005, visceral fat: p = 0.010). We found that the metabolic profile associated with rs588709 resembled that of a TM6SF2 variant impacting very low-density lipoprotein (VLDL) secretion and was only partially similar to that of a HMGCR variant. This suggests that the effect of rs588709 on VLDL lipids may arise due to altered phospholipid rather than cholesterol metabolism. The rs588709 was also nominally associated with circulating concentrations of omega-3 fatty acids in interaction with visceral fat and PC(16:0/2:0), and these fatty acid measures showed robust associations with white matter microstructure. Overall, the present study provides evidence that the DHCR24 locus may link peripheral metabolism to brain microstructure, an association with implications for cognitive impairment.

DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

The association between resting-state functional magnetic resonance imaging and aortic pulse-wave velocity in healthy adults.

Resting-state functional magnetic resonance imaging (rs-fMRI) is frequently used to study brain function; but, it is unclear whether BOLD-signal fluctuation amplitude and functional connectivity are associated with vascular factors, and how vascular-health factors are reflected in rs-fMRI metrics in the healthy population. As arterial stiffening is a known age-related cardiovascular risk factor, we investigated the associations between aortic stiffening (as measured using pulse-wave velocity [PWV]) and rs-fMRI metrics. We used cardiac MRI to measure aortic PWV (an established indicator of whole-body vascular stiffness), as well as dual-echo pseudo-continuous arterial-spin labeling to measure BOLD and CBF dynamics simultaneously in a group of generally healthy adults. We found that: (1) higher aortic PWV is associated with lower variance in the resting-state BOLD signal; (2) higher PWV is also associated with lower BOLD-based resting-state functional connectivity; (3) regions showing lower connectivity do not fully overlap with those showing lower BOLD variance with higher PWV; (4) CBF signal variance is a significant mediator of the above findings, only when averaged across regions-of-interest. Furthermore, we found no significant association between BOLD signal variance and systolic blood pressure, which is also a known predictor of vascular stiffness. Age-related vascular stiffness, as measured by PWV, provides a unique scenario to demonstrate the extent of vascular bias in rs-fMRI signal fluctuations and functional connectivity. These findings suggest that a substantial portion of age-related rs-fMRI differences may be driven by vascular effects rather than directly by brain function.

Visceral fat-related systemic inflammation and the adolescent brain: a mediating role of circulating glycerophosphocholines.

OBJECTIVE: Life-long maintenance of brain health is important for the prevention of cognitive impairment in older age. Low-grade peripheral inflammation associated with excess visceral fat (VF) may influence brain structure and function. Here we examined (i) if this type of inflammation is associated with altered white-matter (WM) microstructure and lower cognitive functioning in adolescents, and (ii) if recently identified circulating glycerophosphocholines (GPCs) can index this type of inflammation and associated variations in WM microstructure and cognitive functioning. SUBJECTS: We studied a community-based sample of 872 adolescents (12-18 years, 48% males) in whom we assessed VF and WM microstructure with magnetic resonance imaging, processing speed with cognitive testing, serum C-reactive protein (CRP, a common marker of peripheral inflammation) with a high-sensitivity assay, and serum levels of a panel of 64 GPCs with advanced mass spectrometry. RESULTS: VF was associated with CRP, and CRP in turn was associated with "altered" WM microstructure and lower processing speed (all p < 0.003). Further, "altered" WM microstructure was associated with lower processing speed (p < 0.0001). Of all 64 tested GPCs, 4 were associated with both VF and CRP (at Bonferroni corrected p < 0.0004). One of them, PC16:0/2:0, was also associated with WM microstructure (p < 0.0001) and processing speed (p = 0.0003), and mediated the directed associations between VF and both WM microstructure (p < 0.0001) and processing speed (p = 0.02). As a mediator, PC16:0/2:0 explained 21% of shared variance between VF and WM microstructure, and 22% of shared variance between VF and processing speed. Similar associations were observed in an auxiliary study of 80 middle-aged adults. CONCLUSIONS: Our results show that VF-related peripheral inflammation is associated with "altered" WM microstructure and lower cognitive functioning already in adolescents, and a specific circulating GPC may be a new molecule indexing this VF-related peripheral inflammation and its influences on brain structure and function.

Glycerophosphocholine Metabolites and Cardiovascular Disease Risk Factors in Adolescents: A Cohort Study.

BACKGROUND: Glycerophosphocholine (GPC) metabolites modulate atherosclerosis and thus risk for cardiovascular disease (CVD). Preclinical CVD may start during adolescence. Here, we used targeted serum lipidomics to identify a new panel of GPCs, and tested whether any of these GPCs are associated, in adolescence, with classical risk factors of CVD, namely excess visceral fat (VF), elevated blood pressure, insulin resistance, and atherogenic dyslipidemia. METHODS: We studied a population-based sample of 990 adolescents (12-18 years, 48% male), as part of the Saguenay Youth Study. Using liquid chromatography-electrospray ionization-mass spectrometry, we identified 69 serum GPCs within the 450 to 680 m/z range. We measured VF with MRI. RESULTS: We identified several novel GPCs that were associated with multiple CVD risk factors. Most significantly, PC16:0/2:0 was negatively associated with VF (P=1.4×10-19), blood pressure (P=7.7×10-5), and fasting triacylglycerols (P=9.0×10-5), and PC14:1/0:0 was positively associated with VF (P=3.0×10-7), fasting insulin (P=5.4×10-32), and triacylglycerols (P=1.4×10-29). The Sobel test of mediation revealed that both GPCs mediated their respective relations between VF (as a potential primary exposure) and CVD risk factors (as outcomes, P values<1.3×10-3). Furthermore, a GPC shown recently to predict incident coronary heart disease in older adults, PC18:2/0:0, was associated with several CVD risk factors in adolescents; these associations were less strong than those with the newly identified GPCs. CONCLUSIONS: We identified novel GPCs strongly associated with multiple CVD risk factors in adolescents. These GPCs may be sensitive indicators of obesity-related risk for CVD outcomes in adults, and may improve biological understanding of CVD risk.

Sex differences in the adolescent brain and body: Findings from the saguenay youth study.

This Mini-Review describes sex differences in 66 quantitative characteristics of the brain and body measured in a community-based sample of 1,024 adolescents 12-18 years of age, members of the Saguenay Youth Study. Using an extensive phenotyping protocol, we have obtained measures in a number of domains, including brain structure, cognition, mental health, substance use, body composition, metabolism, cardiovascular reactivity, and life style. For each measure, we provide estimates of effect size (Cohen's d) and sex-specific correlations with age (Pearson R). In total 59 of the 66 characteristics showed sex differences (at a nominal P < 0.05), with small (32), medium-sized (13), and large (11) effects. Some, but not all, of these sex differences increase during adolescence; this appears to be the case mostly for anatomical and physiological measures. © 2016 Wiley Periodicals, Inc.

Opportunistic Screening of Low Bone Mineral Density From Standard X-Rays.

BACKGROUND: Osteoporosis, characterized by loss of bone mineral density (BMD), is underscreened. Osteoporosis and low bone mass are diagnosed by a BMD T-score ≤ -2.5, and between -1.0 and -2.5, respectively, at the femoral neck or lumbar vertebrae (L1-4), using dual energy x-ray absorptiometry (DXA). The ability to estimate BMD at those anatomic sites from standard radiographs would enable opportunistic screening of low BMD (T-score < -1) in individuals undergoing x-ray for any clinical indication. METHODS: Radiographs of the lumbar spine, thoracic spine, chest, pelvis, hand, and knee, with a paired DXA acquired within 1 year, were obtained from community imaging centers (62,023 x-ray-DXA pairs of patients). A software program called Rho was developed that uses x-ray, age, and sex as inputs, and outputs a score of 1 to 10 that corresponds with the likelihood of low BMD. The program's performance was assessed using receiver-operating characteristic analyses in three independent test sets, as follows: patients from community imaging centers (n = 3,729; 83% female); patients in the Canadian Multicentre Osteoporosis Study (n = 1,780; 71% female); and patients in the Osteoarthritis Initiative (n = 591; 50% female). RESULTS: The areas under the receiver-operating characteristic curves were 0.89 (0.87-0.90), 0.87 (0.85-0.88), and 0.82 (0.79-0.85), respectively, and subset analyses showed similar results for each sex, body part, and race. CONCLUSION: Rho can opportunistically screen patients at risk of low BMD (at femoral neck or L1-4) from radiographs of the lumbar spine, thoracic spine, chest, pelvis, hand, or knee.

An evaluation of early cardiometabolic risk factors in children and adolescents with Turner syndrome.

BACKGROUND AND OBJECTIVES: Turner syndrome (TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra-myocellular lipid between young TS girls and an age- and BMI-standard deviation scores (SDS)-matched healthy female cohort. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. Nineteen TS and 17 control girls (13.7 ± 2.5 vs 12.7 ± 3.4 years of age, respectively, P = 0.30). Multiple-sample oral glucose tolerance test with measurement of fasting insulin, LDL, HDL, triglycerides, adiponectin and highly sensitive C-reactive protein (hsCRP) was performed. Subcutaneous adipose tissue, visceral adipose tissue intramyocellular lipid levels evaluated by magnetic resonance techniques. Insulin secretion (IS), sensitivity (Si) and the insulin secretion-sensitivity index (ISSI-2) were calculated from oral glucose tolerance test data. RESULTS: Five TS and no controls had impaired fasting glucose or impaired glucose tolerance; none had type 2 diabetes mellitus. Insulin sensitivity and insulin secretion were similar between groups; ISSI-2 was lower in TS (923.5 ± 307.3 vs 659.1 ± 387.3; P = 0.03). TS girls had higher blood pressure (82.5 ± 13.6 vs 73.5 ± 5.5 mmHg; P = 0.0146), waist circumference (76.0 ± 11.8 vs 65.9 ± 9.7; P = 0.0087) and subcutaneous adipose tissue (135.6 ± 88.6 vs 69.3 ± 59.9; P = 0.01) than controls. Visceral adipose tissue, intramyocellular lipid levels and adiponectin were not different between groups. TS girls also had higher triglycerides (1.1 ± 0.6 vs 0.7 ± 0.3; P = 0.003), total cholesterol (4.4 ± 0.7 vs 3.9 ± 0.4; P = 0.02) and hsCRP (2.0 ± 1.9 vs 0.8 ± 0.3; P = 0.01). CONCLUSIONS: TS girls exhibit more cardiometabolic risk factors and reduced beta cell function compared with age- and BMI-SDS-matched girls. Increased awareness of early risk of type 2 diabetes mellitus and hypertension in TS girls is needed.

Sex continuum in the brain and body during adolescence and psychological traits.

Many traits of the brain and body show marked sex differences, but the distributions of their values overlap substantially between the two sexes. To investigate variations associated with biological sex, beyond binary differences, we create continuous sex scores capturing the inter-individual variability in phenotypes. In an adolescent cohort (n = 1,029; 533 females), we have generated three sex scores based on brain-body traits: 'overall' (48 traits), 'pubertal' (26 traits) and 'non-pubertal' (22 traits). We then conducted sex-stratified multiple linear regressions (adjusting for age) using sex scores to test associations with sex hormones, personality traits and internalizing-externalizing behaviour. Higher sex scores (that is, greater 'femaleness') were associated with lower testosterone in males only, as well as lower extraversion, higher internalizing and lower externalizing in both sexes. The associations with testosterone, internalizing and externalizing were driven by pubertal sex scores, underscoring the importance of adolescence in shaping within-sex individual variability.

Thickness of the cerebral cortex shows positive association with blood levels of triacylglycerols carrying 18-carbon fatty acids.

Perturbations in fatty acid (FA) metabolism as well as thinning of the cerebral cortex have been associated with cognitive decline in the elderly. Predominant FAs in the brain are docosahexaenoic acid (DHA) and arachidonic acid (ARA). Approximately 2-8% of esterified DHA and 3-5% of esterified ARA in the brain are replaced daily. DHA and ARA are derivatives of 18-carbon essential FAs, α-linolenic acid and linoleic acid, that must be imported into the brain from the circulation. In blood, FAs are primarily transported in triacylglycerols (TAGs) from which they can be released at the blood-brain-barrier and transported inside the brain. We show that circulating levels of TAGs carrying 18-carbon FAs are positively associated with cortical thickness in middle-aged adults. These associations are stronger in cortical regions with higher expression of genes regulating long-chain FA metabolism and cellular membranes, and cortical thickness in the same regions may be related to cognitive performance.

Sex Differences in Blood Pressure Hemodynamics in Middle-Aged Adults With Overweight and Obesity.

High blood pressure (BP) is the strongest modifiable risk factor for cardiovascular disease. Overweight/obesity is a major risk factor of high BP. Multiple sex differences exist in mechanistic pathways that increase BP in overweight/obesity. They may result in a sex-specific pattern of BP hemodynamics-males and females may vary in the relative contributions of stroke volume, total peripheral resistance (TPR), and heart rate to higher BP. We investigated this possibility in a population-based sample of middle-aged adults (36-65 years). The total sample (n=618) included 289 males and 329 females; 79% of males and 66% of females were overweight. In all, we measured BP, stroke volume, TPR, and heart rate beat-by-beat during a 52-minute protocol that included changes in posture and mental stress. We assessed the relative contributions of stroke volume, TPR, and heart rate to BP at each minute of the protocol. We observed marked sex differences in BP hemodynamics in overweight/obese individuals: the main determinant of higher BP was TPR in males (49% versus only 35% in females, P=0.008), whereas it was stroke volume in females (51% versus only 35% in males, P=0.006). These sex differences were most apparent when standing or sitting at rest. No such differences were seen in normal-weight individuals in whom the main determinant of higher BP was TPR in both sexes. Our study suggests that, in middle-aged adults, marked sex differences exist in BP hemodynamics, contributing to high BP in overweight/obese but not normal-weight individuals. As such, this study may contribute to precision medicine in hypertension.

Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

CONTEXT: Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown. OBJECTIVE: To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation. DESIGN: Genome-wide association study (GWAS). SETTING AND PARTICIPANTS: Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years). MAIN OUTCOME MEASURES: Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement. RESULTS: This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization. CONCLUSION: A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood.

A high-fat diet promotes depression-like behavior in mice by suppressing hypothalamic PKA signaling.

Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders. Using lipidomic and transcriptomic methods, we identified a mechanism that links exposure to a high-fat diet (HFD) in mice with alterations in hypothalamic function that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3', 5'-cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and increased the concentration of free fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary-induced depression phenotype. These findings suggest that dietary intake of saturated fats disrupts hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.

Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.

Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.

The association among skeletal muscle phosphocreatine recovery, adiposity, and insulin resistance in children.

BACKGROUND: Obesity is associated with cardiometabolic disturbances, which may have significant implications for musculoskeletal health and exercise tolerance. OBJECTIVE: We sought to determine the association between muscle structure, function, and metabolism in adolescents across the weight spectrum. METHODS: This cross-sectional case-control study included overweight and obese participants (n = 24) 8-18 years of age with a body mass index (BMI) ≥ 85th percentile for age and gender, and non-obese participants (n = 24) with a BMI < 85th percentile. Body composition, physical activity, peak aerobic capacity, cardiometabolic blood markers and insulin resistance (measured by the homeostatic model assessment of insulin resistance, HOMA-IR), skeletal muscle mitochondrial oxidative capacity (via 31 Phosphorous-Magnetic Resonance Spectroscopy, 31 P-MRS, to assess phosphocreatine (PCr) recovery after exercise), and extramyocellular and intramyocellular lipid (IMCL) levels (via 1 Hydrogen-MRS) were assessed. Stepwise regression was performed to examine the factors associated with oxidative capacity. RESULTS: bese and overweight patients had similar age, height, and physical activity to non-obese controls, but obese and overweight participants exhibited higher insulin resistance. Obese and overweight participants had longer PCr recovery than non-obese controls following 5x30s of moderate-intensity exercise (51.2 ± 20.1 s vs. 23.9 ± 7.5 s, p = 0.004). In univariate correlation analysis, impaired PCr recovery was associated with a higher BMI z-score (rs = 0.51, p < 0.001), circulating triglycerides (rs = 0.41, p = 0.005), and HOMA-IR (rs = 0.46, p = 0.001). In stepwise multivariate regression analysis, impaired PCr recovery was associated with a higher BMI z-score (ß = 0.47, p = 0.002), but not insulin resistance (ß = 0.07, p = 0.07) or circulating triglycerides (ß = 0.16 p = 0.33). CONCLUSION: A slower phosphocreatine recovery following aerobic exercise is strongly associated with increasing adiposity. A slower metabolic recovery following aerobic exercise stress suggests that endurance exercise training in obese adolescents may be an optimal strategy to target exercise intolerance in this cohort.

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage.

Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

Hypoxia Inducible Factor-1α in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease

Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α (HIF-1α), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1α in astrocytes and myeloid cells in EAE, HIF-1α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1α to disease pathogenesis remains unclear. Here we show that although HIF-1α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1α in myelination and T-cell-specific HIF-1α in EAE, our results demonstrate a tightly regulated cellular specificity for HIF-1α contribution in nervous system pathogenesis.

CYP17A1 and Blood Pressure Reactivity to Stress in Adolescence.

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12-18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P = 8.3 × 10(-6)). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.