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Johnson, L. A.

Publications and source records attributed to Johnson, L. A..

At least 19 recordsLinked to original sources

Fast Generalized Longitudinal Functional Principal Components Analysis with Applications to Population-Level Neuronal Dynamics

Functional data are widely collected across many fields. One approach for modeling functional data collected across repeated measures is longitudinal functional PCA (LFPCA), which allows for the decomposition of variability at multiple levels. However, existing estimation approaches for LFPCA can be computationally demanding for large or high-dimensional datasets. Here, we propose fast generalized LFPCA, a novel estimation technique that bins data along the functional domain and fits a marginal mixed model at each bin. Simulation results show that the proposed method is orders of magnitude faster than existing techniques while achieving similar accuracy, making LFPCA scalable to datasets with more densely sampled observations and larger sample sizes. We apply the proposed technique to model neuronal firing rate data both on and off deep brain stimulation (DBS) to investigate how the intervention modulates population-level neuronal activity. Our results suggest that the vast majority of between-neuron variation can be explained by four principal components, which relate to individual differences in neuronal firing as well as the arm manipulation paradigm under study. We also find that DBS significantly increases the variability of firing activity, likely driven by increased firing from a subset of neurons in response to DBS, a novel insight not obtained in previous analyses. Code to implement the proposed method and run simulation studies is included in the supplement.

neuroscience↗

Closed-head injury produces a delayed, region-specific defect in glucose-carbon routing at the pyruvate branchpoint in APP/PS1 KI mice

Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly 13C-labeled glucose ([U-13C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.

neuroscience↗

Spontaneous eye behavior is an objective marker of parkinsonian severity

Eye behavior disruption is reported in Parkinson's disease (PD), but its correlation with disease severity has not been well examined. Here, in a nonhuman primate model of PD, we show that spontaneous eye behavior is impaired in parkinsonism and correlates with clinical rating scores and subthalamic beta oscillatory activity. These findings suggest that spontaneous eye behavior could serve as an objective, non-invasive biomarker of parkinsonian severity.

neuroscience↗

Brf1-Mediated RNA Polymerase III Activity Limits Murine Gammaherpesvirus Spread

RNA polymerase III (Pol III) activity is upregulated during herpesvirus infection, yet the functional consequences of this response remain poorly understood. To investigate the role of host Pol III transcription during murine gammaherpesvirus 68 (MHV68) infection, we depleted the Pol III transcription factor Brf1, an essential component of the TFIIIB complex required for transcription from Type I and Type II Pol III promoters. Brf1 depletion enhanced MHV68 replication during low multiplicity of infection (MOI) conditions, resulting in increased viral gene expression, viral protein accumulation, infectious virion production, and extracellular viral genome copies. These effects were confirmed to be Brf1-specific through rescue with an siRNA-resistant Brf1 construct. In contrast, Brf1 depletion produced only modest effects during high-MOI infection, suggesting that Brf1-dependent antiviral activity is most important during multistep viral spread. Transcriptomic analysis revealed accelerated induction of interferon-responsive genes early during infection in Brf1-deficient cells, followed by enhanced host transcript depletion at later stages, consistent with amplified host shutoff. Genetic disruption of the RIG-I/MAVS signaling pathway failed to abolish Brf1 antiviral activity, indicating that this phenotype is independent of MAVS-dependent interferon signaling. Finally, plaque assays demonstrated that Brf1-deficient cells supported larger plaques and increased plaque numbers, suggesting enhanced viral spread and/or entry. Together, our results reveal an unexpected role for Brf1-dependent Pol III activity in controlling gammaherpesvirus spread and suggest that virus-induced Pol III activation contributes to host antiviral defense.

microbiology↗

Anti-amyloid immunotherapy drives APOE4 specific increases in glial reactivity, perivascular immune activation, and ARIA-like events

Anti-amyloid antibodies represent the first disease modifying therapeutics for Alzheimers disease (AD). Adoption of these novel treatments has been slowed by the occurrence of amyloid related imaging abnormalities (ARIA) - treatment-associated edema (ARIA-E) or microhemorrhages (ARIA-H) that disproportionately affect carriers of the E4 allele of apolipoprotein E (APOE). With E4 carriers comprising nearly 70% of the AD population, there is a critical need to understand the unique vulnerability of E4 carriers to these events. To address this gap, we utilized the EFAD mouse model - which expresses human APOE isoforms on the 5xFAD background of amyloidosis - to directly compare the effects of anti-amyloid therapy across APOE genotypes. 9-month-old E2, E3, and E4FAD mice received weekly injections of chimeric Aducanumab (chAdu) or IgG control for 12 weeks, to assess APOE isoform-specific effects on amyloid dynamics, ARIA-H-like microhemorrhages, and underlying cellular and transcriptomic responses. E4FAD mice demonstrated plaque reductions with accompanying increases in microhemorrhages (measured on both MRI and histology), and increases in microglial and astrocyte reactivity - especially in the perivascular compartment. Additionally, vascular branching analysis and parallel single cell and spatial transcriptomics revealed a loss of vascular plasticity and increased inflammatory and immune signaling in the neurovascular units of E4FAD mice. Together, these findings suggest the cerebrovasculature of E4s is uniquely susceptible to antibody mediated vascular damage and provide immunological targets for the assessment or mitigation of ARIA risk in this highest need population

neuroscience↗

Parkinsonism disrupts the population-level organization of cortical dynamics

Parkinsons disease (PD) is marked by impairments in voluntary movement, including prolonged movement preparation and execution, yet how parkinsonism alters neural processing to produce these deficits remains unresolved. Prior work examining M1 spiking activity in parkinsonian states has largely characterized firing-rate changes and motor representations at the level of individual neurons, with inconsistent results and limited insight into population-level organization. Here we investigated how parkinsonism reshapes the population-level organization of neural activity in M1 during movement. We simultaneously recorded large populations of neurons from M1 in two nonhuman primates performing reaching tasks before and after induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the parkinsonian state, both preparation and reach durations were significantly prolonged. Population-level analyses revealed that parkinsonism increased the dimensionality of M1 activity during both preparation and movement and reduced the orthogonality between preparatory and movement-related subspaces. Moreover, trial-by-trial variability in reach duration was explained by the alignment of the preparatory and reach subspaces, indicating the functional role of subspace orthogonality. Together, these findings suggest that parkinsonism disrupts the population-level organization of cortical dynamics across computations, providing a population-level framework linking altered cortical dynamics to the movement-related dysfunction observed in PD.

neuroscience↗

Coupled beta and high-frequency oscillations emerge from synchronized bursting in a minimal model of the parkinsonian subthalamic nucleus

Local field potentials recorded from the subthalamic nucleus (STN) in Parkinson's disease (PD) exhibit a distinctive multiscale spectral signature: exaggerated beta-band oscillations (13-30 Hz) coupled to high-frequency oscillations (HFOs, 200-400 Hz), with HFO amplitude being phase-locked to the beta cycle. This phase-amplitude coupling (PAC) has been identified as a promising biomarker of the parkinsonian state, yet no biophysical model has explained how it emerges, what determines the HFO frequency, or how HFOs can exist without beta modulation in the medicated STN. Here we show that a heterogeneous population of excitatory Izhikevich neurons with recurrent coupling produces three dynamical regimes: (i) asynchronous tonic firing, (ii) asynchronous bursting, in which neurons burst individually producing broadband HFO power but without coherent population-level PAC, and (iii) synchronous bursting, which gives rise to beta-HFO PAC. The regimes are governed by two biophysically interpretable parameters that capture complementary effects of dopamine depletion: one reflecting changes in intrinsic neuronal excitability, the other reflecting changes in synaptic coupling strength. The transition from asynchronous to synchronous bursting in this model captures the emergence of pathological STN neuronal activity in the parkinsonian state. HFO peak frequency varies continuously across the two-parameter landscape, suggesting a possible mechanism of the clinically observed shift from slow (200-300 Hz) to fast (300-400 Hz) HFOs between medication states. The character of the synchronization transition depends on baseline excitability, ranging from a sharp co-emergence of bursting and synchrony at low excitability to a decoupled transition at intermediate excitability, where the bursting fraction saturates while the population synchronization continues to increase with coupling. We also extend the model to include reciprocal coupling to an inhibitory population of globus pallidus externa (GPe)-like neurons and report a similar asynchronous-to-synchronous bursting transition and beta-HFO PAC emerging in the STN population, with the beta rhythm being set by the delay in the synaptic coupling between the two populations. The model generates testable predictions for future clinical and experimental studies, provides a numerical dissection of how mesoscopic LFP features map onto microscopic neuronal dynamics, and serves as a computational building block for future circuit-level models that may inform brain stimulation strategies tailored to the patient-specific dynamical state of the STN.

neuroscience↗

Transcranial Alternating Current Stimulation can disrupt or reestablish neural entrainment in a primate model of Parkinson's disease

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method which can affect brain oscillations by inducing neuronal entrainment through modulation of spike timings. tACS has high potential for clinical applications in many neurological disorders in which the stimulation can be delivered to modulate oscillatory activity and disrupt pathological brain oscillations. For instance, in Parkinsons Disease (PD), electrophysiological activity in the motor network often exhibits excessive and hyper-synchronized beta oscillations. However, the development of tACS as a therapeutic intervention for pathological oscillations requires the prior establishment of physiologically effective stimulation parameters. We recorded neuronal activity in the motor cortical area of three parkinsonian non-human primates and examined the influence of tACS-induced electric fields on neural firing patterns. We found that weak extracellular electric fields first disrupt beta-band spike timing patterns by changing the preferred spiking phase of neurons but eventually reestablish neural entrainment with altered phase preferences when electric fields are high. Additionally, we show that frequency-matched stimulation, when stimulation frequency corresponds to endogenous oscillatory activity, significantly enhances neural entrainment. Thus, tACS exhibits significant potential for controlling and modulating pathological oscillatory patterns in many neurological disorders such as PD.

neuroscience↗

Knockout of Perilipin 2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer's Disease Stimuli

Lipid droplets (LDs) are emerging as critical regulators of cellular metabolism and inflammation, with their accumulation in microglia linked to aging and neurodegeneration. Perilipin 2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores, and in peripheral tissues its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. However, the role of Plin2 in brain-resident microglia remains undefined. Here, we used CRISPR-engineered Plin2 knockout (KO) BV2 microglia to investigate the contribution of Plin2 to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia exhibited markedly reduced LD burden under both basal and oleic acid-loaded conditions. Functionally, this was associated with enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity in the absence of Plin2. Transcriptomic analyses revealed genotype-specific responses to amyloid-{beta} (A{beta}), particularly in pathways related to mitochondrial metabolism. Seahorse assays confirmed that Plin2 KO cells adopt a distinct bioenergetic profile, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare respiratory reserve, and a blunted glycolytic response to A{beta}. Together, these findings identify Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss alleviating lipid accumulation, improving phagocytic function, and altering A{beta}-induced metabolic reprogramming. Targeting Plin2 may therefore represent a potential strategy to modulate microglial metabolism and function in aging and neurodegeneration.

neuroscience↗

Sleep firing rate homeostasis is disrupted in mild parkinsonism

Sleep-associated downscaling of neuronal firing, i.e., firing rate homeostasis (FRH), is essential for restorative sleep. Sleep dysfunction is common in Parkinsons disease (PD), but FRH has not been investigated. Here, using a within-subject design in the nonhuman primate model of PD, we report that thalamocortical FRH is disrupted in parkinsonism. These findings can inform therapeutic approaches tailored towards normalizing FRH to reestablish restorative sleep in PD.

neuroscience↗

A gut-selective Axl Inhibitor Attenuates Intestinal Fibrosis in myofibroblast cell models and the Mouse S. Typhimurium Model in vivo

BackgroundIntestinal fibrosis leads to intestinal failure in Crohns disease (CD), but we have no effective antifibrotic medical therapies. Axl inhibitors have been studied in the treatment of fibrosis in liver and lung, but not in intestine. The objective of this study was to test whether CCG264341, a novel gut selective Axl inhibitor, can treat intestinal fibrosis in both in vitro and in vivo IBD fibrosis models. MethodsCCD-18Co human intestinal myofibroblasts were co-treated with 100 ng/mL Fas ligand (FASL) and a dose range of CCG264341 for 5 hours, or treated with TGF{beta} for 48 hours, followed by protein isolation and western blot analysis. Tissue PK experiments in mice were performed to select the CCG264341 dose for the in vivo model. For the in vivo model, intestinal fibrosis was induced in CBA/J mice by S. typhimurium infection, Mice were treated with CCG264341 daily during days 4-21 after S. typhimurium infection, followed by sac on day 22. Cecum and proximal colon (affected tissue) was analyzed by gross pathology, histological fibrosis scoring, qRT-PCR, western blot, and immunofluorescence staining. ResultsCCG264341 at doses of 0.1/0.3/1.0 {micro}M sensitizes CCD-18Co myofibroblasts to FasL-mediated apoptosis over FasL alone, and this effect was dose dependent, per cleaved Parp protein quantitation. With TGF{beta} treatment, Axl protein expression was increased, along with Col1a1, MYLK, SMA and FN1 protein upregulation. CCG264341 could reduce AXL protein and downstream signal p-Akt expression with dose dependence, along with reduced Col1a1, MYLK, SMA and FN1 protein expression after treatment with CCG264341 treatment. The highest CCG264341 concentrations were detected in the terminal ileum after 5 hours oral feeding in PK experiments, and much lower compound concentrations could still be detected in other organs. A dose of 25mg/kg daily was selected for the mouse intestinal fibrosis treatment model. In the murine S. typhimurium model, AXL protein and downstream signals p-Akt, p-Erk and P-Stat3 expression were all increased in colon and cecum, with the expression of the fibrosis related proteins upregulated. CCG264341 treatment significantly inhibited AXL expression, with downstream signals and fibrosis related protein downregulation. By blinded histopathology with H&E and trichrome staining, as well as immunofluorescence for fibrosis related proteins, colon fibrosis scores significantly decreased. ConclusionsCCG264341is a partially gut selective Axl inhibitor. This compound could play a therapeutic role in IBD fibrosis models. Further work to improve gut selectivity and anti-fibrotic efficacy are needed, but this is a promising pathway for future therapeutic intervention in Crohns disease.

immunology↗

APOE4 alters the lipid droplet proteome and modulates droplet dynamics

Excess lipid droplet (LD) accumulation is associated with several pathological states, including Alzheimers disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics contribute to pathophysiology of these disorders remains unclear. Apolipoprotein E (ApoE) is a droplet associated protein with a common risk variant (E4) that confers the largest increase in genetic risk for late-onset AD. E4 is associated with both increased neuroinflammation and excess LD accumulation. In the current study, we sought to quantitatively profile the lipid and protein composition of LDs between the neutral E3 and risk variant E4, to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human E3 or E4 were injected with saline or lipopolysaccharide (LPS), and after 24 hours, hepatic lipid droplets were isolated for proteomic and lipidomic analyses. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with a concomitant increase in phosphatidylcholine species, and overall, the baseline profile of E4 LDs resembled that of the LPS-treated groups. Quantitative proteomics showed that LDs from E4 mice are enriched for proteins involved in protein/vesicle transport but have decreased levels of proteins involved in fatty acid {beta}-oxidation. Interestingly, proteins associated with LDs showed substantial overlap with previously published lists of AD postmortem tissue and microglia omics studies, suggesting a potential role for LDs in modulating AD risk or progression. Given this, we exposed primary microglia from the same E3 or E4 mice to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate LD formation and its impact on the cells immune state. Microglia from E4 mice accumulated more LDs in every condition tested - at baseline and following addition of fatty acids, LPS stimulation, or nN2As. E4 microglia also secreted significantly more cytokines (TNF, IL-1{beta}, IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions, yet showed a blunted response to LPS. In sum, these results suggest that E4 microglia accumulate more LDs compared to E3 microglia and that E4 is associated with a basal LD composition that resembles a pro-inflammatory cell. Together with the high overlap of the LD proteome with established AD-associated datasets, these data further support the idea that alterations in LD dynamics, particularly within microglia, may contribute to the increased risk for AD associated with APOE4.

physiology↗

Parkinsonism disrupts neuronal modulation in the pre-supplementary motor area during movement preparation

Multiple studies suggest that Parkinsons disease (PD) is associated with changes in neuronal activity throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts neuronal activity in the pre-supplementary motor area (pre-SMA), an area in medial frontal cortex involved in movement planning and motor control. In this study, single unit activity was recorded in the pre-SMA of two non-human primates during a visually cued reaching task in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In the naive state neuronal discharge rates were dynamically modulated prior to the presentation of the instructional go-cue. In a subset of these modulated cells, the magnitude of modulation correlated linearly with reaction time (RT). In the parkinsonian state, however, modulation of discharge rates in the pre-SMA was disrupted and the predictive encoding of RT was significantly diminished. These findings add to our understanding of the role of pre-SMA in motor behavior and suggest that disrupted encoding in this cortical area contributes to the alteration of early preparatory and pre-movement processes that are present in Parkinsons disease. SIGNIFICANCE STATEMENTGoal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in people with Parkinsons disease is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in pre-supplementary motor area (pre-SMA) neuronal firing to the pathogenesis of motor disturbances in parkinsonism.

neuroscience↗

Impairment of Neuronal Activity in the Dorsolateral Prefrontal Cortex Occurs Early in Parkinsonism

BackgroundParkinsons disease (PD) is often characterized by altered rates and patterns of neuronal activity in the sensorimotor regions of the basal ganglia thalamocortical network. Little is known, however, regarding how neuronal activity in the executive control network of the brain changes in the parkinsonian condition. ObjectiveInvestigate the impact of parkinsonism on neuronal activity in the dorsolateral prefrontal cortex (DLPFC), a key region in executive control, during a go/nogo reaching task. MethodsUsing a within-subject design, single and multi-unit neuronal activity was recorded in the DLPFC of a nonhuman primate before and after the induction of mild parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). ResultsCoincident with development of mild parkinsonian motor signs, there was a marked reduction in the percentage of DLPFC cells with significant task-related firing rate modulation during go and nogo conditions. ConclusionsThese results suggest that DLPFC dysfunction may occur early in parkinsonism and contribute to cognitive impairments and disrupted executive function often observed in PD patients.

neuroscience↗

Kir6.2-KATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal KATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. HighlightsO_LIGlycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. C_LIO_LIWith Kir6.2-KATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. C_LIO_LIKir6.2-KATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/581817v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@11640c6org.highwire.dtl.DTLVardef@1f6a88corg.highwire.dtl.DTLVardef@b38daborg.highwire.dtl.DTLVardef@1a061f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism

Increasing evidence associates slow-wave sleep (SWS) dysfunction with neurodegeneration. Using a within-subject design in the nonhuman primate model of Parkinsons disease (PD), we found that reduced SWS quantity in mild parkinsonism was accompanied by elevated beta and reduced delta power during SWS in the motor cortex. Our findings support excessive beta oscillations as a mechanism for SWS dysfunction and will inform development of neuromodulation therapies for enhancing SWS in PD.

neuroscience↗

Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression

BackgroundInflammatory cells within atherosclerotic lesions secrete various proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. The relative contributions of specific proteases to atherogenesis is not well understood. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We have previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as an endogenous modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models. ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after systemic administration to Apoe-/- mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr-/- mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

physiology↗

Sex and APOE Genotype Influence Respiratory Function Under Hypoxic and Hypoxic-Hypercapnic Conditions

The apolipoprotein (APOE) gene has been studied due to its influence on Alzheimers disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often co-present with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenge. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.

neuroscience↗