Compensatory Response Research Articles

Phillyrin Inhibits Isoproterenol-Induced Cardiac Hypertrophy Via P38 and NF-κB Pathways

Cardiac hypertrophy (CH) is the main compensatory response to chronic heart stress and often progresses to a decompensation state potentially leading to heart failure. Phillyrin (PHI) is a novel compound derived from Forsythia, which has shown anti-inflammatory and anti-virus activities as well as renal protective effects on diabetic nephropathy. Therefore, we investigated the effects of PHI on CH induced by isoproterenol (ISO). Cardiac hypertrophy was induced by ISO in vivo, and the H9C2 cells were treated with ISO. PHI treatment alleviated CH in isoproterenol-induced mice in 7 and 14 days. Echocardiography showed that the PHI improved ISO-induced CH heart function and structure. PHI significantly decreased heart weight/body weight (HW/BW) and heart weight/tibia length (HW/TL) ratios and improved left ventricular (LV) function in ISO-treated mice. Hematoxylin and eosin staining revealed cardiomyocyte areas of the ISO group were significantly increased, and PHI was significantly reduced at 7 and 14 days, PHI-100 groups showed significantly better improvements than PHI-50. Sirius red staining indicated PHI significantly decreased collagen deposition in heart cross-sections induced by ISO, and PHI repressed ISO-induced cTn-I and NT-proBNP expression in mouse serum. In vitro data from H9C2 cells showed that PHI decreased cell areas and total cell protein levels in cells induced by ISO, whereas ANP, BNP, IL-6, and IL-1β expression was significantly inhibited by PHI. Also, PHI simultaneously inhibited P65 and P38 phosphorylation in vivo and in vitro. In conclusion, this study demonstrated the protective effect of PHI on CH in in vivo and in vitro, and this effect was related to the suppression of inflammation through the activation of the P38/NF-κB pathway.

Somatostatin: From a supporting actor to the protagonist to explain the long-term effect of sleeve gastrectomy on glucose metabolism

BackgroundBariatric/metabolic surgery has become the most effective treatment against type 2 Diabetes mellitus (T2DM). The role of many gastrointestinal hormones in T2DM has been proposed, but the pathophysiological models described vary greatly depending on the anatomical rearrangements after surgery. We focus on somatostatin as a common factor in two of the most commonly performed surgical procedures in a healthy rodent model. We performed sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and also an experimental surgery without gastric involvement (intestinal resection of 50 % jejunum-ileum portion –IR50 %). Methods: We used five groups of Wistar rats: fasting control, sham-operated, SG-operated, RYGB-operated and IR50-operated. We analysed several parameters 4 and 23 weeks after surgery: plasma SST-14/28 fractions, plasma glucose, insulin release and SST-producing cell expression in the duodenum and pancreatic islets. Results: Numerous SST-producing cells in the duodenum but a low number in the pancreas and a long-term loss of glucose tolerance were observed in SG and RYGB animals. Additionally, a high plasma SST-28 fraction was found in animals after SG but not after RYGB. Finally, IR50 animals showed no differences versus controls. Conclusions: In our SG model the amplitude of insulin response after metabolic surgeries, is mediated by SST-28 plasma levels derived from the proportional compensatory effect of gastric SST-producing tissue ablation. In addition, a strong compensatory response to the surgical loss of gastric SST-producing cells, leads to long-term loss of insulin production after SG but not in the others.

A Compensatory Response to the Problem of Evil: Revisited

In this essay, I revisit the univocity thesis, Sterba’s analogy between God and a leader of a politically liberal society, and, most fundamentally, whether the existence of horrendous evils is logically compatible with the existence of a good God. I concede that the typical appeals to free will and greater goods defenses to block the logical problem of evil are not sufficient because they do not adequately address the horrendous evils that are all too much a feature of human existence. While acknowledging that a compensatory response to the problem of evil is suggested by several important philosophers, I rely most centrally on the work of Marilyn McCord Adams. In so doing, I defend the thesis that the existence of a good God is logically compatible with the existence of horrendous evils, given God’s capacity to absorb, defeat, or engulf it.

Adiponectin and Interleukin-33: Possible Early Markers of Metabolic Syndrome

Adiponectin is one of the most important molecules in the body's compensatory response to the development of insulin resistance. By trying to maintain insulin sensitivity, increase insulin secretion and prevent inflammation, adiponectin tries to maintain glucose homeostasis. Interleukin-33, which belongs to the group of alarmins, also promotes insulin secretion. Interleukin-33 might be either pro-inflammatory or anti-inflammatory depending on the disease and the model. However, interleukin-33 has shown various protective effects in CVD, obesity and diabetes. The aim of our study was to investigate the association between adiponectin and interleukin-33 in patients with metabolic syndrome. As expected, all patients with metabolic syndrome had worse parameters that represent the hallmark of metabolic syndrome compared to the control group. In the subgroup of patients with low adiponectin, we observed less pronounced characteristics of metabolic syndrome simultaneously with significantly higher values of interleukin-33 compared to the subgroup of patients with high adiponectin. Our findings suggested that adiponectin might be an early marker of metabolic syndrome that emerges before anthropomorphic, biochemical and clinical parameters. We also suggest that both interleukin-33 and adiponectin may be used to predict the inflammatory status in the early stage of metabolic syndrome.

Trauma & TYPOI: The Fourth Gospel as Warning Not Example

There are at least four traumatic events that likely lie behind the Gospel of John: (1) Jesus’ death and inaccessibility, (2) the destruction of the Jerusalem Temple, (3) the Johannine community’s excommunication from the synagogue, and (4) the loss of the Beloved Disciple. Evidence of all of these traumas can be found in the Gospel itself and, as extant, the Gospel exhibits a number of strategies for addressing these experiences of suffering. Working from Gaston Bachelard’s observations regarding literature produced in response to suffering, this paper outlines the textual evidence for each of these experiences of suffering, notes the responses to them that the Gospel displays, and seeks briefly to evaluate the responses for the TYPOI (patterns/examples/warnings) they provide. In short, the Fourth Gospel employs psychologically attractive, compensatory responses to experiences of loss. However, it deploys in parallel a toxic cocktail of anti-Jewish polemic, condemnation of “the world”, and self-protective, sectarian insularity. Regarding whether the text’s trauma response can be viewed as exemplary for ethically-minded Christians, Desmond Tutu’s 2009 statement, “there are certain parts [of the Bible] which you have to say no to”, is directly applicable, while the warning the text’s example suggests is significant.

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n=30) and replicated key findings in a second cohort (n=31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx-/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Acute and chronic neurodegeneration a continuum in the establishment of neurodegenerative disorders

As worldwide human population grows in number and gets older, disabilities derived from neurological disorders become morepresent. In addition to the lack of efforts directed to preventive actions against the occurrence and establishment of a neurologicaldisorder, will lead governmental institutions to face an increasing requirement for treatment and rehabilitations programs to dealwith consequences caused by these disorders. Demonstrating the importance that neuroscientists focus on the design of newparadigms that allow the identification of a potential prophylactic and therapeutic treatment for these disorders, is a key step. In thepresent work, authors did an overall bibliographical review and general description of the mechanisms involved on acute andchronic neurodegenerative damage, trying to show the common points on both kind of damage. Therefore, to identify andsubstantiate the key characteristics that link degenerative progression from an acute damage to the establishment of a chronicalneurological disorder. Highlighting the value of early interventions on acute neurological damage, centered on neuroprotection viacell signaling pathways that could mediate or prevent neuronal damage. Consequently, to spot and notice the repercussions andtranscendence that research in therapeutic strategies focus on mimic and potentiate the compensatory response unchained after aneurological damage, is a key factor to find new treatments for these disorders.

Higher systolic blood pressure is specifically associated with better islet beta-cell function in T2DM patients with high glycemic level

BackgroundPatients with type 2 diabetes mellitus (T2DM) usually have higher blood viscosity attributed to high blood glucose that can decrease blood supply to the pancreas. A mild increase in blood pressure (BP) has been reported as a potential compensatory response that can maintain blood perfusion in the islet. However, how BP influences beta-cell function in T2DM subjects remains inconsistent. This study aimed to examine the relationship between BP and beta-cell function in patients with T2DM under different HbA1c levels.MethodsThis is a cross-sectional study of 615 T2DM patients, whose clinical data were extracted from hospital medical records. Beta-cell function was assessed by insulin secretion-sensitivity index-2 (ISSI2). Multivariable linear regression analysis and restricted cubic splines (RCS) analysis were performed to identify the association between systolic BP (SBP) and ISSI2. Mediation analysis was performed to determine whether higher SBP could reduce blood glucose by enhancing beta-cell function.ResultsAfter adjustment of potential confounders, in participants with HbA1c ≥ 10%, the SBP between 140 to150 mmHg had the highest log ISSI2 (b = 0.227, 95% CI 0.053–0.402), an association specific to participants with < 1 year duration of diabetes. RCS analyses demonstrated an inverted U-shaped association between SBP and ISSI2 with the SBP at 144 mmHg corresponding to the best beta-cell function. This higher SBP was “paradoxically” associated with lower 2 h postprandial blood glucose (PBG) when SBP < 150 mmHg that was almost exclusively mediated by ISSI2 (mediating effect = − 0.043, 95%CI − 0.067 to − 0.018; mediating effect percentage = 94.7%, P < 0.01). SBP was however not associated with improvement in ISSI2 or 2 h PBG in participants with HbA1c < 10%.ConclusionsIn early stage of diabetes, a slightly elevated SBP (140–150 mmHg) was transiently associated with better beta-cell function in T2DM patients with HbA1c ≥ 10% but not in those with HbA1c < 10%.

Preservation of shortening velocity and power output in single muscle fibres from patients with idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders of skeletal muscle causing weakness and disability. Utilizing single fibre contractility studies, we have previously shown that contractility is affected in muscle fibres from individuals with IIMs. For the current study, we hypothesized that a compensatory increase in shortening velocity occurs in muscle fibres from individuals with IIMs in an effort to maintain power output. We performed in vitro single fibre contractility studies to assess force-velocity relationships and maximum shortening velocity (Vmax) of muscle fibres from individuals with IIMs (25 type I and 58 type IIA) and healthy controls (66 type I and 27 type IIA) and calculated maximum power output (Wmax) for each fibre. We found significantly higher Vmax (mean ± SEM) of fibres from individuals with IIMs, for both type I (1.40 ± 0.31 fibre lengths/s, n = vs. 0.63 ± 0.13 fibre lengths/s; p = 0.0019) and type IIA fibres (2.00 ± 0.17 fibre lengths/s vs 0.77 ± 0.10 fibre lengths/s; p < 0.0001). Furthermore, Wmax (mean ± SEM) was maintained compared to fibres from healthy controls, again for both type I and type IIA fibres (4.10 ± 1.00 kN/m2·fibre lengths/s vs. 2.00 ± 0.16 kN/m2·fibre lengths/s; p = ns and 9.00 ± 0.64 kN/m2·fibre lengths/s vs. 6.00 ± 0.67 kN/m2·fibre lengths/s; p = ns respectively). In addition, type I muscle fibres from individuals with IIMs was able to develop maximum power output at lower relative force. The findings of this study suggest that compensatory responses to maintain power output, including increased maximum shortening velocity and improved efficiency, may occur in muscle of individuals with IIMs. The mechanism underlying this response is unclear, and different hypotheses are discussed.

Identification of novel immune-related targets mediating disease progression in acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear. An integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo. The numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10-3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10-8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation. In summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression.

Noninvasive Monitoring of Simulated Hemorrhage and Whole Blood Resuscitation

Hemorrhage is the leading cause of preventable death from trauma. Accurate monitoring of hemorrhage and resuscitation can significantly reduce mortality and morbidity but remains a challenge due to the low sensitivity of traditional vital signs in detecting blood loss and possible hemorrhagic shock. Vital signs are not reliable early indicators because of physiological mechanisms that compensate for blood loss and thus do not provide an accurate assessment of volume status. As an alternative, machine learning (ML) algorithms that operate on an arterial blood pressure (ABP) waveform have been shown to provide an effective early indicator. However, these ML approaches lack physiological interpretability. In this paper, we evaluate and compare the performance of ML models trained on nine ABP-derived features that provide physiological insight, using a database of 13 human subjects from a lower-body negative pressure (LBNP) model of progressive central hypovolemia and subsequent progressive restoration to normovolemia (i.e., simulated hemorrhage and whole blood resuscitation). Data were acquired at multiple repressurization rates for each subject to simulate varying resuscitation rates, resulting in 52 total LBNP collections. This work is the first to use a single ABP-based algorithm to monitor both simulated hemorrhage and resuscitation. A gradient-boosted regression tree model trained on only the half-rise to dicrotic notch (HRDN) feature achieved a root-mean-square error (RMSE) of 13%, an R2 of 0.82, and area under the receiver operating characteristic curve of 0.97 for detecting decompensation. This single-feature model's performance compares favorably to previously reported results from more-complex black box machine learning models. This model further provides physiological insight because HRDN represents an approximate measure of the delay between the ABP ejected and reflected wave and therefore is an indication of cardiac and peripheral vascular mechanisms that contribute to the compensatory response to blood loss and replacement.

Ozone impairs endogenous compensatory responses in allergic asthma

Asthma is a chronic inflammatory airway disease characterized by acute exacerbations triggered by inhaled allergens, respiratory infections, or air pollution. Ozone (O3), a major component of air pollution, can damage the lung epithelium in healthy individuals. Despite this association, little is known about the effects of O3 and its impact on chronic lung disease. Epidemiological data have demonstrated that elevations in ambient O3 are associated with increased asthma exacerbations. To identify mechanisms by which O3 exposure leads to asthma exacerbations, we developed a two-hit mouse model where mice were sensitized and challenged with three common allergens (dust mite, ragweed and Aspergillus fumigates, DRA) to induce allergic inflammation prior to exposure to O3 (DRAO3). Changes in lung physiology, inflammatory cells, and inflammation were measured. Exposure to O3 following DRA significantly increased airway hyperreactivity (AHR), which was independent of TLR4. DRA exposure resulted in increased BAL eosinophilia while O3 exposure resulted in neutrophilia. Additionally, O3 exposure following DRA blunted anti-inflammatory and antioxidant responses. Finally, there were significantly less monocytes and innate lymphoid type 2 cells (ILC2s) in the dual challenged DRA-O3 group suggesting that the lack of these immune cells may influence O3-induced AHR in the setting of allergic inflammation. In summary, we developed a mouse model that mirrors some aspects of the clinical course of asthma exacerbations due to air pollution and identified that O3 exposure in the asthmatic lung leads to impaired endogenous anti-inflammatory and antioxidant responses and alterations inflammatory cell populations.

Effects of Morning or Evening Narrow-band Blue Light on the Compensation to Lens-induced Hyperopic Defocus in Chicks.

Exposure to blue light before bedtime is purported to be deleterious to various aspects of human health. In chicks, blue evening light stimulated ocular growth, suggesting a role in myopia development. To further investigate this hypothesis, we asked if brief blue light altered the compensatory responses to hyperopic defocus. Previous work showed that several hours' evening exposure to blue light stimulated ocular growth in chicks, but morning exposure was only effective at a lower illuminance. By contrast, rearing in blue light has inhibited ocular growth in untreated eyes and eyes exposed to form deprivation or defocus. We studied the effects of brief exposures to blue light on the compensation to hyperopic defocus. Chicks wore monocular negative lenses (-10 D) starting at age 10 days. They were subsequently exposed to blue light (460 nm) for 4 hours in the morning or evening for 8 to 9 days ("dim," 200 lux[morning, n = 9; evening, n = 11]; "bright," 600 lux[morning, n = 8; evening, n = 20]); controls wore lenses in white light (n = 14). Ultrasonography was done on days 1, 5, 8, and 9 for "evening" groups and days 1, 6, and 8 for "morning." All data are reported as interocular differences (experimental minus fellow eyes). Refractions were measured on the last day. For evening exposure, dim blue light enhanced the axial compensation at all times (change in axial length: day 6: 465 vs. 329 μm/9 days, analysis of variance P < .001, P = .03; day 9: 603 vs. 416 μm/9 days, analysis of variance P < .001; P < .05). Bright blue light had a transient inhibitory effect (day 5: 160 vs. 329 μm; P < .005). Refractive errors were consistent with axial growth, with dim causing more myopia than bright (-9.4 vs. -4.7 D; P < .05). Morning blue light had no significant effect. We speculate that these findings reflect a complex interaction between illuminance, defocus, and time of day.

Body and visual instabilities functionally modulate implicit reaching corrections

Hierarchical brain-information-processing schemes have frequently assumed that the flexible but slow voluntary action modulates a direct sensorimotor process that can quickly generate a reaction in dynamical interaction. Here we show that the quick visuomotor process for manual movement is modulated by postural and visual instability contexts that are related but remote and prior states to manual movements. A preceding unstable postural context significantly enhanced the reflexive manual response induced by a large-field visual motion during hand reaching while the response was evidently weakened by imposing a preceding random-visual-motion context. These modulations are successfully explained by the Bayesian optimal formulation in which the manual response elicited by visual motion is ascribed to the compensatory response to the estimated self-motion affected by the preceding contextual situations. Our findings suggest an implicit and functional mechanism that links the variability and uncertainty of remote states to the quick sensorimotor transformation.

Dietary- but not exercise-induced acute iso-energetic deficit result in short-term appetitive compensatory responses in adolescents with obesity

BackgroundProducing negative energy balance rests on the creation of energy deficits that have been shown, depending on their modality, to induce potential appetitive compensatory responses. The aim of this study was to compare energy intake (EI), appetite feelings, and the hedonic responses to equivalent acute energy deficits induced by exercise versus energy restriction in adolescents with obesity. MethodsIn a within-participants design, seventeen adolescents with obesity (12–16 years, Tanner stage 3–5, 9 males) randomly completed three conditions: i) control (CON); ii) deficit induced by diet only (Def-EI); and iii) deficit induced by exercise only (Def-EX). Lunch was calibrated to generate a 400-kcal deficit in Def-EI and remained similar in CON and Def-EX. A 400-kcal deficit was created through a cycling bout set at 65% VO2peak in Def-EX. Ad libitum EI, macronutrient intake and relative EI (REI) were assessed at dinner, subjective appetite sensations taken at regular intervals, and food reward measured before dinner. ResultsFood intake at dinner was greater in Def-EI (1112 ± 265 kcal) compared to CON (983 ± 277 kcal; p = 0.005) and Def-EX (1009 ± 281 kcal; p = 0.025). Absolute protein and lipid intake were significantly higher in Def-EI (52.4 ± 9.5 g and 36.8 ± 8.9 g respectively) compared with both CON (44.9 ± 12.6 g; p = 0.001 and 33.8 ± 10.1 g; p = 0.002 respectively) and Def-EX (47.3 ± 11.8 g, p = 0.018, 35.4 ± 10.1 g, p = 0.036 respectively). Area under the curve (AUC) for hunger, desire to eat and prospective food consumption were significantly higher in Def-EI compared with both CON (p = 0.0001) and Def-EX (p = 0.0001). AUC for fullness was significantly lower on Def-EI compared with CON and Def-EX (p = 0.0001). Implicit wanting for sweet food was significantly lower on Def-EX (p = 0.031), relative to CON. ConclusionAppetitive compensatory responses that are observed after iso-caloric energy restriction in adolescents with obesity are absent with acute exercise, which could contribute to optimize our impact on short-term energy balance.

Compensatory Transcriptional Response of Fischerella thermalis to Thermal Damage of the Photosynthetic Electron Transfer Chain.

Key organisms in the environment, such as oxygenic photosynthetic primary producers (photosynthetic eukaryotes and cyanobacteria), are responsible for fixing most of the carbon globally. However, they are affected by environmental conditions, such as temperature, which in turn affect their distribution. Globally, the cyanobacterium Fischerella thermalis is one of the main primary producers in terrestrial hot springs with thermal gradients up to 60 °C, but the mechanisms by which F. thermalis maintains its photosynthetic activity at these high temperatures are not known. In this study, we used molecular approaches and bioinformatics, in addition to photophysiological analyses, to determine the genetic activity associated with the energy metabolism of F. thermalis both in situ and in high-temperature (40 °C to 65 °C) cultures. Our results show that photosynthesis of F. thermalis decays with temperature, while increased transcriptional activity of genes encoding photosystem II reaction center proteins, such as PsbA (D1), could help overcome thermal damage at up to 60 °C. We observed that F. thermalis tends to lose copies of the standard G4 D1 isoform while maintaining the recently described D1INT isoform, suggesting a preference for photoresistant isoforms in response to the thermal gradient. The transcriptional activity and metabolic characteristics of F. thermalis, as measured by metatranscriptomics, further suggest that carbon metabolism occurs in parallel with photosynthesis, thereby assisting in energy acquisition under high temperatures at which other photosynthetic organisms cannot survive. This study reveals that, to cope with the harsh conditions of hot springs, F. thermalis has several compensatory adaptations, and provides emerging evidence for mixotrophic metabolism as being potentially relevant to the thermotolerance of this species. Ultimately, this work increases our knowledge about thermal adaptation strategies of cyanobacteria.

Translational potential of JAX humanized‐APOE mice model: Accelerated midlife endocrine aging in hAPOEε4/4 females

AbstractBackgroundAge, female sex and APOEε4 genotype are the greatest Alzheimer’s (AD) risk factors, with a stronger APOEε4 link to AD in women. The APOE‐sex interaction is also evident in hAPOE mouse models where APOEε4 induces more severe neurodegeneration and cognitive deficits in female mice. However, the mechanisms by which these two risk factors converge to disrupt brain function remain elusive.MethodTo investigate effect of APOE genotype on midlife endocrine aging, 6‐, 9‐ and 15‐month hAPOEε3/3 and hAPOEε4/4 female mice were stratified into 3 different endocrine aging groups based on vaginal cytology profiles: regular cyclers (consistent 4–5 day cycles), irregular cyclers (of 6–9 day cycles), and acyclic (no cycling &gt;9 days). Plasma levels of metabolomic makers were measured. Brain mitochondrial function was quantified.ResulthAPOEε4/4 females exhibited accelerated endocrine aging evidenced by increased magnitude of brain metabolic defect coupled with inability to mount an adaptive bioenergetic response. Systems biology of endocrine aging initially identified in perimenopausal rat model were replicated in the hAPOEε3/3 mouse model. In contrast, hAPOEε4/4 females exhibited accumulation of adipose tissue with high plasma triglyceride and accelerated ketone body dysregulation during perimenopausal transition, indicating deficits in adaptive metabolic response required for sustaining brain metabolic demand during aging. Further, hAPOEε4/4 females exhibited greater perimenopause‐ and menopause‐induced brain mitochondrial dysfunction.ConclusionOutcomes of these analyses provide a plausible mechanistic pathway underlying the greater risk of AD in APOEε4 females. Further, these data indicate that the bioenergetic crisis underlying metabolic reprogramming in brain are greater in the APOEε4 female brain while compensatory adaptive responses are compromised. These findings provide a rational mechanistic precision medicine approach to intervene during midlife to prevent or delay the onset of the prodromal / preclinical stage of AD.This work was supported by NIA grants P01‐AG026572 Project 2 to RDB and Animal Core to TW.

Regional neuronal compensation in early and late stages of the Alzheimer’s trajectory

AbstractBackgroundGlucose hypermetabolism is suggested to occur as a compensatory response to early neuronal damage[1]. Hypermetabolism has been shown to arise in the prodromal phase of Alzheimer’s disease development as a mechanism to prevent against cognitive deficits or as a compensatory mechanism to maintain the neuronal function amidst of other neurodegenerative process. Here we aimed to evaluate whether there is regional glucose hypermetabolism as a proxy to neuronal function in response to tau deposition in different stages of Alzheimer’s disease.Method139 amyloid positive cognitively impaired subjects were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (n = 44 diagnosed with Alzheimer’s disease, n = 95 mild cognitive impairment). All subjects had [18F]AV1451 and [18F]FDG PET imaging and an anatomical T1 weighted MRI scan. PET scans were coregistered to the respective anatomical scan and normalised to MNI space in SPM12. Standard uptake value ratio (SUVr) images were created using cerebellar grey matter and pons uptake as reference region for [18F]AV1451 and [18F]FDG, respectively. Voxel‐wise linear regression was conducted between[18F]AV1451 and [18F]FDG. Pearson’s correlations were conducted between regions displaying a positive association.ResultVoxel‐wise analysis revealed a correlation between higher glucose metabolism and tau deposition localised to the pre and post‐central gyrus in our cognitively impaired cohort. We found evidence that higher tau deposition and higher glucose metabolism were associated in the left and right post‐central gyrus in Alzheimer’s subjects (n=44, r=0.361 p=0.016 and r=0.327 p=0.030, respectively). A significant correlation was observed in both the left and right pre‐central gyrus (n=95, r=0.418 p&lt;0.001 and r=0.361 p&lt;0.001, respectively) as well as the left (r=0.384 p&lt;0.001)and right post‐central gyrus (r=0.324 p=0.001) in subjects diagnosed with mild cognitive impairment.ConclusionThis correlation between higher tau and higher glucose metabolism in pre‐and post‐central gyrus implies that there is still neuronal compensation occurring in response to tau deposition both in early and later stages of the disease process (Braak stages V‐VI). This suggests that neuronal compensation occurs on a regional basis throughout the Alzheimer’s disease trajectory and may reflect the ability of neurons to still respond to an effective treatment.

Comparison of apical and basolateral Cu treatment for iron-related gene regulation during deferoxamine induced iron deficiency.

Intestinal copper transporter (Atp7a) mutant-brindled mice with systemic Cu deficiency had elevated Cu levels in enterocyte cells without any perturbation of iron-regulating genes, suggesting that blood Cu level might be important for intestinal iron homeostasis during iron deficiency (ID). We hypothesized that the blood Cu level and polarization (apical and basolateral) of enterocyte cells might be important regulators for the compensatory response on the regulation of genes in enterocyte cells during iron deficiency. We grew Caco-2 cells on a bicameral cell culture plate to mimic the human intestine system and on a regular tissue culture plate. Iron deficiency was induced by deferoxamine (DFO). The cells were treated with Cu and Cu with Fe following mRNA expressions of DMT1, FPN, TFR, and ANKRD37 were analyzed. Our main finding was that basolateral treatment of Cu significantly reduced mRNA expressions of iron-regulated genes, including DMT1, FPN, TFR, and ANKRD37, compared to DFO-treated and DFO with apical Cu-treated groups in both bicameral and regular tissue culture plates. Cu level in the basolateral side of Caco-2 cells significantly influenced the intracellular gene regulation in DFO-induced iron-deficient condition, and polarization of the cells might be important factor gene regulation in enterocyte cells.

The Role of Alzheimer’s disease relevant Tau modifications in Neurodegeneration and Mitochondrial dysfunction

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder whose pathological hallmarks include intraneuronal neurofibrillary tangles (NFTs) composed of the microtubule‐associated protein Tau. Tau isolated from AD brain exhibits abnormally high levels of post‐translational modifications (PTMs) including phosphorylation and acetylation at specific epitopes that increase with disease severity and age. In addition, mitochondrial dysfunction is an early feature of AD, and abnormal, toxic tau PTMs may contribute to disease pathogenesis. A major bottleneck in understanding the mechanisms behind the neurotoxicity of pathological forms of Tau is the lack of genetically tractable models that can recapitulate the effects of Tau PTMs in a short time frame without artifacts associated with Tau overexpression.MethodHuman 0N4R Tau (wild type) was expressed in touch receptor neurons through single‐copy gene insertion. Mutations were introduced into the single‐copy tau transgene through CRISPR‐Cas9 genome editing, including T231E and T231A, to mimic phosphorylation and phospho‐ablation of a commonly observed pathological epitope, respectively, and K274/281Q, to mimic disease‐associated lysine acetylation. We then assessed their impact on age‐dependent response to light touch, neurodegeneration, and mitochondrial parameters such as abundance, morphology, trafficking, and turnover, using fluorescent biosensors including mito‐mKeima.ResultUnlike existing tau overexpression models, C. elegans single‐copy expression of wild type human tau did not elicit overt pathological phenotypes at baseline. However, strains expressing disease associated PTM‐mimetics (T231E and K274/281Q) exhibited reduced touch sensation and neuronal morphological abnormalities that increased with age. Remarkably, the PTM‐mimetics selectively impaired mitophagy following mitochondrial oxidative stress, but had no effect on macroautophagy, and furthermore reduced mitolysosomal trafficking.ConclusionSingle copy expression limits pathological phenotypes to strains expressing disease‐associated Tau mutants. In addition to overt pathology, these mutants eliminate oxidative stress‐induced mitophagy and reduce trafficking of mitolysosomes. Our findings highlight a selective mechanism through which disease‐associated Tau PTMs may suppress compensatory responses to mitochondrial stress that occur with age and provide a new perspective into the pathogenic mechanisms underlying AD.