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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 379 records · Page 21
All sourcesNASA NTRSDOE OSTI
NASA NTRS2002

Mechanism of blood pressure and R-R variability: insights from ganglion blockade in humans

Spontaneous blood pressure (BP) and R-R variability are used frequently as 'windows' into cardiovascular control mechanisms. However, the origin of these rhythmic fluctuations is not completely understood. In this study, with ganglion blockade, we evaluated the role of autonomic neural activity versus other 'non-neural' factors in the origin of BP and R-R variability in humans. Beat-to-beat BP, R-R interval and respiratory excursions were recorded in ten healthy subjects (aged 30 +/- 6 years) before and after ganglion blockade with trimethaphan. The spectral power of these variables was calculated in the very low (0.0078-0.05 Hz), low (0.05-0.15 Hz) and high (0.15-0.35 Hz) frequency ranges. The relationship between systolic BP and R-R variability was examined by cross-spectral analysis. After blockade, R-R variability was virtually abolished at all frequencies; however, respiration and high frequency BP variability remained unchanged. Very low and low frequency BP variability was reduced substantially by 84 and 69 %, respectively, but still persisted. Transfer function gain between systolic BP and R-R interval variability decreased by 92 and 88 % at low and high frequencies, respectively, while the phase changed from negative to positive values at the high frequencies. These data suggest that under supine resting conditions with spontaneous breathing: (1) R-R variability at all measured frequencies is predominantly controlled by autonomic neural activity; (2) BP variability at high frequencies (> 0.15 Hz) is mediated largely, if not exclusively, by mechanical effects of respiration on intrathoracic pressure and/or cardiac filling; (3) BP variability at very low and low frequencies (< 0.15 Hz) is probably mediated by both sympathetic nerve activity and intrinsic vasomotor rhythmicity; and (4) the dynamic relationship between BP and R-R variability as quantified by transfer function analysis is determined predominantly by autonomic neural activity rather than other, non-neural factors.

Non-NASA Center↗
NASA NTRS1997

Cerebral blood flow velocity and cranial fluid volume decrease during +Gz acceleration

Cerebral blood flow (CBF) velocity and cranial fluid volume, which is defined as the total volume of intra- and extracranial fluid, were measured using transcranial Doppler ultrasonography and rheoencephalography, respectively, in humans during graded increase of +Gz acceleration (onset rate: 0.1 G/s) without straining maneuvers. Gz acceleration was terminated when subjects' vision decreased to an angle of less than or equal to 60 degrees, which was defined as the physiological end point. In five subjects, mean CBF velocity decreased 48% from a baseline value of 59.4 +/- 11.2 cm/s to 31.0 +/- 5.6 cm/s (p<0.01) with initial loss of peripheral vision at 5.7 +/- 0.9 Gz. On the other hand, systolic CBF velocity did not change significantly during increasing +Gz acceleration. Cranial impedance, which is proportional to loss of cranial fluid volume, increased by 2.0 +/- 0.8% above the baseline value at the physiological end point (p<0.05). Both the decrease of CBF velocity and the increase of cranial impedance correlated significantly with Gz. These results suggest that +Gz acceleration without straining maneuvers decreases CBF velocity to half normal and probably causes a caudal fluid shift from both intra- and extracranial tissues.

NASA Discipline Cardiopulmonary↗
NASA NTRS2000

Effect of head-down-tilt bed rest and hypovolemia on dynamic regulation of heart rate and blood pressure

Adaptation to head-down-tilt bed rest leads to an apparent abnormality of baroreflex regulation of cardiac period. We hypothesized that this "deconditioning response" could primarily be a result of hypovolemia, rather than a unique adaptation of the autonomic nervous system to bed rest. To test this hypothesis, nine healthy subjects underwent 2 wk of -6 degrees head-down bed rest. One year later, five of these same subjects underwent acute hypovolemia with furosemide to produce the same reductions in plasma volume observed after bed rest. We took advantage of power spectral and transfer function analysis to examine the dynamic relationship between blood pressure (BP) and R-R interval. We found that 1) there were no significant differences between these two interventions with respect to changes in numerous cardiovascular indices, including cardiac filling pressures, arterial pressure, cardiac output, or stroke volume; 2) normalized high-frequency (0.15-0.25 Hz) power of R-R interval variability decreased significantly after both conditions, consistent with similar degrees of vagal withdrawal; 3) transfer function gain (BP to R-R interval), used as an index of arterial-cardiac baroreflex sensitivity, decreased significantly to a similar extent after both conditions in the high-frequency range; the gain also decreased similarly when expressed as BP to heart rate x stroke volume, which provides an index of the ability of the baroreflex to alter BP by modifying systemic flow; and 4) however, the low-frequency (0.05-0.15 Hz) power of systolic BP variability decreased after bed rest (-22%) compared with an increase (+155%) after acute hypovolemia, suggesting a differential response for the regulation of vascular resistance (interaction, P < 0.05). The similarity of changes in the reflex control of the circulation under both conditions is consistent with the hypothesis that reductions in plasma volume may be largely responsible for the observed changes in cardiac baroreflex control after bed rest. However, changes in vasomotor function associated with these two conditions may be different and may suggest a cardiovascular remodeling after bed rest.

Non-NASA Center↗
NASA NTRS2000

Validity of VO(2 max) in predicting blood volume: implications for the effect of fitness on aging

A multiple regression model was constructed to investigate the premise that blood volume (BV) could be predicted using several anthropometric variables, age, and maximal oxygen uptake (VO(2 max)). To test this hypothesis, age, calculated body surface area (height/weight composite), percent body fat (hydrostatic weight), and VO(2 max) were regressed on to BV using data obtained from 66 normal healthy men. Results from the evaluation of the full model indicated that the most parsimonious result was obtained when age and VO(2 max) were regressed on BV expressed per kilogram body weight. The full model accounted for 52% of the total variance in BV per kilogram body weight. Both age and VO(2 max) were related to BV in the positive direction. Percent body fat contributed <1% to the explained variance in BV when expressed in absolute BV (ml) or as BV per kilogram body weight. When the model was cross validated on 41 new subjects and BV per kilogram body weight was reexpressed as raw BV, the results indicated that the statistical model would be stable under cross validation (e.g., predictive applications) with an accuracy of +/- 1,200 ml at 95% confidence. Our results support the hypothesis that BV is an increasing function of aerobic fitness and to a lesser extent the age of the subject. The results may have implication as to a mechanism by which aerobic fitness and activity may be protective against reduced BV associated with aging.

NASA Discipline Cardiopulmonary↗
NASA NTRS2000

Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome

The postural tachycardia syndrome (POTS) is characterized clinically by orthostatic lightheadedness and tachycardia. When these patients perform a Valsalva maneuver, there is an excessive blood pressure increment after cessation of the maneuver (phase IV) that is sometimes associated with headaches. It is not known whether excessive phase IV is due to excessive peripheral vascular tone (an alpha-adrenergic mechanism) or is a manifestation of increased beta-adrenergic tone (hyperadrenergic state). The authors undertook a pharmacologic study evaluating the effect of intravenous phentolamine (alpha-adrenergic antagonist) and propranolol (beta-adrenergic antagonist) on the different phases of the Valsalva maneuver in a group of patients with POTS and age-matched normal control subjects. Patients with POTS had mean phases, when compared with controls, that were characterized by more negative II_E (p = 0.07), smaller II_L (p = 0.04), and significantly larger phase IV (p = 0.001). The effect of phentolamine was qualitatively and quantitatively different in POTS when compared with controls. Ten mg phentolamine in controls resulted in a significant accentuation of phase II_E (p = 0.001), attenuation of phase II_L (p = 0.002), and increase of phase IV (57.6 vs 30.7 mm Hg; p = 0.025). These changes resembled those of patients with POTS at baseline. In patients with POTS, the phase II abnormalities, already present, were further accentuated (p <0.001), and phase IV became smaller (50.6 vs 73.8 mm Hg; p = 0.09). Propranolol had no significant effect on phases II_E and II_L, but significantly reduced phase IV in both controls (p <0.05) and in patients with POTS (p <0.001) and improved the headache symptoms, when present, during and after phase IV. The authors conclude that phase IV is mainly under beta-adrenergic regulation and that the exaggerated phase IV in POTS is a result of a hyperadrenergic state.

Non-NASA Center↗
NASA NTRS1999

A fluid--structure interaction finite element analysis of pulsatile blood flow through a compliant stenotic artery

A new model is used to analyze the fully coupled problem of pulsatile blood flow through a compliant, axisymmetric stenotic artery using the finite element method. The model uses large displacement and large strain theory for the solid, and the full Navier-Stokes equations for the fluid. The effect of increasing area reduction on fluid dynamic and structural stresses is presented. Results show that pressure drop, peak wall shear stress, and maximum principal stress in the lesion all increase dramatically as the area reduction in the stenosis is increased from 51 to 89 percent. Further reductions in stenosis cross-sectional area, however, produce relatively little additional change in these parameters due to a concomitant reduction in flow rate caused by the losses in the constriction. Inner wall hoop stretch amplitude just distal to the stenosis also increases with increasing stenosis severity, as downstream pressures are reduced to a physiological minimum. The contraction of the artery distal to the stenosis generates a significant compressive stress on the downstream shoulder of the lesion. Dynamic narrowing of the stenosis is also seen, further augmenting area constriction at times of peak flow. Pressure drop results are found to compare well to an experimentally based theoretical curve, despite the assumption of laminar flow.

Non-NASA Center↗
NASA NTRS1997

Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects

Normative data are limited on autonomic function tests, especially beyond age 60 years. We therefore evaluated these tests in a total of 557 normal subjects evenly distributed by age and gender from 10 to 83 years. Heart rate (HR) response to deep breathing fell with increasing age. Valsalva ratio varied with both age and gender. QSART (quantitative sudomotor axon-reflex test) volume was consistently greater in men (approximately double) and progressively declined with age for all three lower extremity sites but not the forearm site. Orthostatic blood pressure reduction was greater with increasing age. HR at rest was significantly higher in women, and the increment with head-up tilt fell with increasing age. For no tests did we find a regression to zero, and some tests seem to level off with increasing age, indicating that diagnosis of autonomic failure was possible to over 80 years of age.

Non-NASA Center↗
NASA NTRS1997

Baroreflex regulation of blood pressure during dynamic exercise

From the work of Potts et al. Papelier et al. and Shi et al. it is readily apparent that the arterial (aortic and carotid) baroreflexes are reset to function at the prevailing ABP of exercise. The blood pressure of exercise is the result of the hemodynamic (cardiac output and TPR) responses, which appear to be regulated by two redundant neural control systems, "Central Command" and the "exercise pressor reflex". Central Command is a feed-forward neural control system that operates in parallel with the neural regulation of the locomotor system and appears to establish the hemodynamic response to exercise. Within the central nervous system it appears that the HLR may be the operational site for Central Command. Specific neural sites within the HLR have been demonstrated in animals to be active during exercise. With the advent of positron emission tomography (PET) and single-photon emission computed tomography (SPECT), the anatomical areas of the human brain related to Central Command are being mapped. It also appears that the Nucleus Tractus Solitarius and the ventrolateral medulla may serve as an integrating site as they receive neural information from the working muscles via the group III/IV muscle afferents as well as from higher brain centers. This anatomical site within the CNS is now the focus of many investigations in which arterial baroreflex function, Central Command and the "exercise pressor reflex" appear to demonstrate inhibitory or facilitatory interaction. The concept of whether Central Command is the prime mover in the resetting of the arterial baroreceptors to function at the exercising ABP or whether the resetting is an integration of the "exercise pressor reflex" information with that of Central Command is now under intense investigation. However, it would be justified to conclude, from the data of Bevegard and Shepherd, Dicarlo and Bishop, Potts et al., and Papelier et al. that the act of exercise results in the resetting of the arterial baroreflex. In addition, if, as we have proposed, the cardiopulmonary baroreceptors primarily monitors and reflexly regulates cardiac filling volume, it would seem from the data of Mack et al. and Potts et al. that the cardiopulmonary baroreceptor is also reset at the beginning of exercise. Therefore, investigations of the neural mechanisms of regulation involving Central Command and cardiopulmonary afferents, similar to those being undertaken for the arterial baroreflex, need to be established.

NASA Discipline Cardiopulmonary↗
NASA NTRS1993

Regulation of central blood volume and cardiac filling in endurance athletes: the Frank-Starling mechanism as a determinant of orthostatic tolerance

Orthostatic intolerance may result from either an abnormally large postural decrease in central blood volume, cardiac filling pressures, and stroke volume, or inadequate neurohumoral responses to orthostasis. Endurance athletes have been reported as having a high incidence of orthostatic intolerance, which has been attributed primarily to abnormalities in baroreflex regulation of heart rate and peripheral resistance. In this review, we present evidence that athletes also have structural changes in the cardiovascular system that although beneficial during exercise, lead to an excessively large decrease in stroke volume during orthostasis and contribute to orthostatic intolerance. A unifying hypothesis based on cardiac mechanics that may explain the divergence of findings in conditions such as bed rest or spaceflight, and short- and long-term endurance training is presented.

Non-NASA Center↗
NASA NTRS1993

Z-DNA binding protein from chicken blood nuclei

A protein (Z alpha) that appears to be highly specific for the left-handed Z-DNA conformer has been identified in chicken blood nuclear extracts. Z alpha activity is measured in a band-shift assay by using a radioactive probe consisting of a (dC-dG)35 oligomer that has 50% of the deoxycytosines replaced with 5-bromodeoxycytosine. In the presence of 10 mM Mg2+, the probe converts to the Z-DNA conformation and is bound by Z alpha. The binding of Z alpha to the radioactive probe is specifically blocked by competition with linear poly(dC-dG) stabilized in the Z-DNA form by chemical bromination but not by B-form poly(dC-dG) or boiled salmon-sperm DNA. In addition, the binding activity of Z alpha is competitively blocked by supercoiled plasmids containing a Z-DNA insert but not by either the linearized plasmid or by an equivalent amount of the parental supercoiled plasmid without the Z-DNA-forming insert. Z alpha can be crosslinked to the 32P-labeled brominated probe with UV light, allowing us to estimate that the minimal molecular mass of Z alpha is 39 kDa.

NASA Discipline Exobiology↗
NASA NTRS1992

The effects of exercise on blood flow with reference to the human cardiovascular system: a finite element study

This paper reports on a theoretical investigation into the effects of vasomotion on blood through the human cardiovascular system. The finite element method has been used to analyse the model. Vasoconstriction and vasodilation may be effected either through the action of the central nervous system or autoregulation. One of the conditions responsible for vasomotion is exercise. The proposed model has been solved and quantitative results of flows and pressures due to changing the conductances of specific networks of arterioles, capillaries and venules comprising the arms, legs, stomach and their combinations have been obtained.

NASA Discipline Cardiopulmonary↗
DOE OSTI2021

Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use

Abstract Extracellular vesicles (EV) are a promising therapeutic tool in regenerative medicine. These particles were shown to accelerate wound healing, through delivery of regenerative mediators, such as microRNAs. Herein we describe an optimized and upscalable process for the isolation of EV smaller than 200 nm (sEV), secreted by umbilical cord blood mononuclear cells (UCB-MNC) under ischemic conditions and propose quality control thresholds for the isolated vesicles, based on the thorough characterization of their protein, lipid and RNA content. Ultrafiltration and size exclusion chromatography (UF/SEC) optimized methodology proved superior to traditional ultracentrifugation (UC), regarding production time, standardization, scalability, and vesicle yield. Using UF/SEC, we were able to recover approximately 400 times more sEV per mL of media than with UC, and upscaling this process further increases EV yield by about 3-fold. UF/SEC-isolated sEV display many of the sEV/exosomes classical markers and are enriched in molecules with anti-inflammatory and regenerative capacity, such as hemopexin and miR-150. Accordingly, treatment with sEV promotes angiogenesis and extracellular matrix remodeling, in vitro. In vivo, UCB-MNC-sEV significantly accelerate skin regeneration in a mouse model of delayed wound healing. The proposed isolation protocol constitutes a significant improvement compared to UC, the gold-standard in the field. Isolated sEV maintain their regenerative properties, whereas downstream contaminants are minimized. The use of UF/SEC allows for the standardization and upscalability required for mass production of sEV to be used in a clinical setting.

Cardoso, Renato M. S.↗
DOE OSTI2022

Fluorescence-coupled micropipette aspiration assay to examine calcium mobilization caused by red blood cell mechanosensing

Abstract Mechanical stimuli such as tension, compression, and shear stress play critical roles in the physiological functions of red blood cells (RBCs) and their homeostasis, ATP release, and rheological properties. Intracellular calcium (Ca 2+ ) mobilization reflects RBC mechanosensing as they transverse the complex vasculature. Emerging studies have demonstrated the presence of mechanosensitive Ca 2+ permeable ion channels and their function has been implicated in the regulation of RBC volume and deformability. However, how these mechanoreceptors trigger Ca 2+ influx and subsequent cellular responses are still unclear. Here, we introduce a fluorescence-coupled micropipette aspiration assay to examine RBC mechanosensing at the single-cell level. To achieve a wide range of cell aspirations, we implemented and compared two negative pressure adjusting apparatuses: a homemade water manometer (− 2.94 to 0 mmH 2 O) and a pneumatic high-speed pressure clamp (− 25 to 0 mmHg). To visualize Ca 2+ influx, RBCs were pre-loaded with an intensiometric probe Cal-520 AM, then imaged under a confocal microscope with concurrent bright-field and fluorescent imaging at acquisition rates of 10 frames per second. Remarkably, we observed the related changes in intracellular Ca 2+ levels immediately after aspirating individual RBCs in a pressure-dependent manner. The RBC aspirated by the water manometer only displayed 1.1-fold increase in fluorescence intensity, whereas the RBC aspirated by the pneumatic clamp showed up to threefold increase. These results demonstrated the water manometer as a gentle tool for cell manipulation with minimal pre-activation, while the high-speed pneumatic clamp as a much stronger pressure actuator to examine cell mechanosensing directly. Together, this multimodal platform enables us to precisely control aspiration and membrane tension, and subsequently correlate this with intracellular calcium concentration dynamics in a robust and reproducible manner.

Wang, Haoqing↗
DOE OSTI2022

Development and performance of a HemeLB GPU code for human-scale blood flow simulation

In recent years, it has become increasingly common for high performance computers (HPC) to possess some level of heterogeneous architecture - typically in the form of GPU accelerators. In some machines these are isolated within a dedicated partition, whilst in others they are integral to all compute nodes - often with multiple GPUs per node - and provide the majority of a machine's compute performance. In light of this trend, it is becoming essential that codes deployed on HPC are updated to execute on accelerator hardware. Here, in this paper, we introduce a GPU implementation of the 3D blood flow simulation code HemeLB that has been developed using CUDA C++. We demonstrate how taking advantage of NVIDIA GPU hardware can achieve significant performance improvements compared to the equivalent CPU only code on which it has been built whilst retaining the excellent strong scaling characteristics that have been repeatedly demonstrated by the CPU version. With HPC positioned on the brink of the exascale era, we use HemeLB as a motivation to provide a discussion on some of the challenges that many users will face when deploying their own applications on upcoming exascale machines.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Changes in Peripheral Blood Regulatory T Cells and IL-6 and IL-10 Levels Predict Response of Pediatric Medulloblastoma and Germ Cell Tumors With Residual or Disseminated Disease to Craniospinal Irradiation

Radiation therapy (RT) modulates immune cells and cytokines, resulting in both clinically beneficial and detrimental effects. The changes in peripheral blood T lymphocyte subsets and cytokines during RT for pediatric brain tumors and the association of these changes with therapeutic outcomes have not been well described.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia

CD19 chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, approximately 20% of patients fail to achieve a complete remission (CR), and some develop severe, life-threatening toxicities. Understanding the biological mechanisms underlying both dysfunctional responses and severe toxicity is essential for optimizing patient management and improving therapeutic efficacy. This study aimed to (1) characterize cytokine profiles associated with dysfunctional responses and severe toxicity following CAR-T infusion, (2) examine the timing and trajectory of cytokine changes in relation to treatment outcomes, and evaluate potential strategies for mitigating toxicity and treatment failure. We conducted a comprehensive analysis of serum cytokine profiles in 86 adult and pediatric patients undergoing autologous CD19 CAR-T therapy for B-ALL. Patients were categorized into three groups: (1) Dysfunctional response—Patients who failed to achieve a minimal residual disease-negative CR (MRD-CR) by Day 63 or who experienced recurrence of CD19+ disease in the setting ongoing CAR-T cell detection before Day 63. (2) Functional response with severe cytokine release syndrome (CRS) and/or neurotoxicity (NTX)—Patients with best response of MRD-CR by Day 63 who experienced grade 3 or higher CRS or NTX. (3) Functional response without severe CRS or NTX—Patients with best response of MRD-CR by Day 63 who did not experience grade =3 CRS or NTX. Cytokine levels were measured during the first-week postinfusion and correlated with treatment efficacy, toxicity outcomes, complete blood counts, and CAR-T expansion dynamics. This analysis aimed to better understand how cytokine profiles relate to patient outcomes and immune responses in CAR-T therapy. Patients with dysfunctional response exhibited decreased neutrophils, platelets, and levels of granulocytic cytokines (suggestive of low bone marrow reserve) alongside elevated pro-inflammatory cytokines by Day 1. Functional response with severe toxicity patients showed a progressive rise in proinflammatory cytokines, reaching similar levels to dysfunctional response patients by Day 7. We observed that high cytokines at both the Day 1 and Day 7 time points were associated with poor survival. These findings remained significant when adjusting for high disease burden, a known predictor of severe inflammatory toxicity and lack of response. Early post-CAR-T infusion inflammation is associated with both dysfunctional response and severe toxicity—even after adjusting for disease burden. This suggests that inflammation, in addition to disease burden, plays a role in determining patient outcome. Therefore, strategies aimed at reducing the pro-inflammatory state prior to or early after CAR-T cell infusion may improve outcomes for R/R B-ALL patients.

Serum cytokines↗
DOE OSTI2024

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment

Circadian misalignment due to night work has been associated with elevated risk for chronic diseases. Here, we investigated the effects of circadian misalignment using shotgun protein profiling of peripheral blood mononuclear cells taken from healthy humans during a constant routine protocol, which was conducted immediately after participants had been subjected to a 3-day simulated night shift schedule or a 3-day simulated day shift schedule. By comparing proteomic profiles between the simulated shift conditions, we identified proteins and pathways that are associated with the effects of circadian misalignment, and observed that insulin regulation pathways and inflammation-related proteins displayed markedly different temporal patterns after simulated night shift. Further, by integrating the proteomic profiles with previously assessed metabolomic profiles in a network-based approach, we found key associations between circadian dysregulation of protein-level pathways and metabolites of interest in the context of chronic metabolic diseases. Overall, our results suggest that circadian misalignment is associated with a tug of war between central clock mechanisms controlling insulin secretion and peripheral clock mechanisms regulating insulin sensitivity, which may lead to adverse long-term outcomes such as diabetes and obesity. Our study provides a molecular-level mechanism linking circadian misalignment and adverse long-term health consequences of night work.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A Copper-Binding Peptide with Therapeutic Potential against Alzheimer′s Disease: From the Blood–Brain Barrier to Metal Competition

Alzheimer’s disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu 2+ and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu 2+ -Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu 2+ binding to the cellular prion protein (PrPC). Therefore, in addition to metal selectivity and blood–brain barrier (BBB) permeability, an emerging challenge for copper chelators is to prevent the formation of neurotoxic Cu 2+ -Aβ species without perturbing the neuroprotective Cu 2+ -PrPC interaction. Previously, we reported the design of a tetrapeptide (TP) that withdraws Cu 2+ from Aβ(1–16) and impacts the Cu 2+ -induced aggregation of Aβ(1–40). In this study, we improved the drug-like properties of TP in a BBB model, evaluated the metal selectivity of the optimized peptide (TP*), and tested its effect on Cu 2+ coordination to PrPC and proteins involved in copper trafficking, such as copper transporter 1 and albumin. Our results show that changing the stereochemistry of the first residue prevents TP degradation in the BBB model and coadministration of TP with a peptide that increases BBB permeability allows its passage through the BBB model. TP* is highly selective toward Cu 2+ in the presence of Zn 2+ ions, transfers Cu 2+ to copper-trafficking proteins, and forms a ternary TP*-Cu 2+ -PrP species that does not perturb the physiological conformation of PrP and displays only a minor impact in the neuroprotective Cu 2+ -dependent interaction of PrPC with the N-methyl-d-aspartate receptor. Overall, these results show that TP* displays desirable features for a copper chelator with therapeutic potential against AD. Moreover, this is the first study that explores the effect of a Cu 2+ chelator with therapeutic potential for AD on Cu 2+ coordination to PrPC (an emerging key player in AD pathology), integrating recent knowledge about metalloproteins involved in AD with the design of copper chelators against AD.

60 APPLIED LIFE SCIENCES↗