Biology subjects

Nishimura, N.

Publications and source records attributed to Nishimura, N..

At least 19 recordsLinked to original sources

bioRxiv2026

GSDMD transcript levels are higher in endothelial than cardiomyocyte compartments across three human heart cohorts

Cardiac GSDMD research has largely centred on cardiomyocytes. We quantified donor-level endothelial-minus-cardiomyocyte differences in two single-nucleus cohorts and one GeoMx spatial cohort, retaining assay-specific scales. GSDMD was higher in endothelial compartments in 42/42, 38/38 and 27/32 donors and ranked, post hoc, at the 94.9th, 95.1st and 97.4th percentiles of the corresponding within-cohort signed-contrast distributions. Although positive direction and complete donor concordance were not unique transcriptome-wide, this hypothesis-led target retained high rank across markedly different reference backgrounds and assay modalities. A fixed eight-transcript panel included both endothelial- and cardiomyocyte-shifted members, arguing against a uniform panel-wide directional shift or simple detection failure. GeoMx provided the most discriminating transcriptome background but remained composition-sensitive. GSDMD transcripts are therefore recurrently higher in endothelial than cardiomyocyte compartments across human-heart cohorts, showing that a cardiomyocyte-only interpretation of human-heart GSDMD transcript signals is incomplete.

cell biology↗

bioRxiv2026

Globin digest and its constituent peptides promote skeletal muscle hypertrophy and enhance physical performance

Globin digest (GD), an acidic protease hydrolysate of hemoglobin, has been recognized for its anti-obesity and glucose-modulating effects; however, its direct anabolic potential in skeletal muscle remains uncharacterized. We evaluated the effects of GD and its constituent peptides on muscle hypertrophy and motor function using zebrafish, mice, and C2C12 myoblasts. Adult zebrafish administered GD (400 mg/kg BW/d) for 1 week showed significantly increased swimming distance (p < 0.05). Similarly, oral administration of GD (1 g/kg BW/d) to C57BL/6J mice for 4 weeks enhanced grip strength and rotarod performance, accompanied by a 1.5-fold increase in myofiber diameter and upregulation of fast-twitch Myh1 (1.9-fold) and Myh2 (1.8-fold) mRNA levels. In vitro, GD dose-dependently (1-100 g/mL) stimulated C2C12 differentiation and MyHC accumulation. Notably, GD did not merely serve as a nutritional nitrogen source; instead, it functioned as a signaling modulator via a specific "relay-like" peptide orchestration. Among six identified sequences, Peptides 3 (WTQR) and 5 (WGK) primarily initiated early-stage commitment by upregulating MyoD and Myf5, whereas Peptides 2 (VVYP) and 6 (FES) accelerated mid-stage maturation. This stage-specific synergy achieved robust myotube hypertrophy that exceeded the efficacy of individual components. These findings demonstrate that GD promotes skeletal muscle hypertrophy and motor function through direct myogenic signaling, establishing a novel foundation for precision sports nutrition to optimize muscle maintenance and physical performance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/728339v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@94675borg.highwire.dtl.DTLVardef@10dbbfaorg.highwire.dtl.DTLVardef@b026eforg.highwire.dtl.DTLVardef@cc4058_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Spatial transcriptomics identifies a translayer architecture of pyroptosis-related transcription in systemic sclerosis skin

Anatomical-layer enrichment does not establish cellular attribution, so correspondence with major-cell-class expression must be tested gene by gene. Systemic sclerosis (SSc) skin is informative because inflammasome- and pyroptosis-related molecules have been reported across epidermal, fibroblast-associated and vascular contexts. Spatial transcriptomics of SSc and control skin, with same-donor single-nucleus profiles from 10 SSc donors, revealed gene-specific correspondence. Across 13 discovery sections, NLRP1, PYCARD and CASP4 were epidermally biased, whereas GSDMD was dermally biased. An independent 10-section SSc cohort supported epidermal NLRP1 (q = 0.0078) and PYCARD (q = 0.043), with directional, non-significant support for CASP4 and GSDMD. Despite epidermal NLRP1 bias, endothelial class-pseudobulk exceeded keratinocyte class-pseudobulk in all 10 donors. Restricted three-class reconstruction reproduced the NLRP1 direction in 1 and 0 of 10 donors under the two fixed dermal weightings and in 0-8 of 10 across a post hoc sweep of the dermal endothelial share; PYCARD and GSDMD were concordant in most donors at every weighting, and CASP4 in no more than 4 of 10. Thus, tissue layer and major cell class are gene-specifically non-equivalent axes of spatial interpretation.

immunology↗

bioRxiv2026

Reprogrammed neutrophils with impaired transit mechanics drive multi-organ capillary stalling after stroke

Beyond the focal brain lesion, stroke causes systemic complications including cardiac failure, pneumonia, renal injury, and sustained immune dysfunction. The source of this multiorgan vulnerability remains unresolved. By imaging over 16,000 vessels of healthy, inflamed and ischemic brains, we identify a circulating neutrophil subpopulation reprogrammed by stroke into a pathological stalling phenotype, occluding capillaries in the brain, heart, kidneys, retina and lungs. Combining transcriptomics, genetic models, integrated microfluidics, cell mechanics assays, and in vivo imaging, we show that this subpopulation exhibits an atypical morphology, increased actin polymerization, and heightened adhesion that impair transit through capillary networks. This phenotype is present in patients with stroke, transmissible by adoptive transfer, and selectively sensitive to inhibition of the Src-family kinase Fgr. Both pharmacological and genetic inactivation of Fgr normalize neutrophil adhesion, reduce capillary stalls, and improve neurological recovery after stroke. These findings identify immune cell transit failure as a systemic driver of post-stroke pathology and a therapeutic target to improve both cerebral and multiorgan outcomes.

neuroscience↗

bioRxiv2025

Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion

1.Breast cancer cells invade mammary adipose tissue during initial stages of metastasis but how the physical properties of adipose tissue regulate this process remains unclear. Here, we combined single cell mechanical characterization of primary adipocytes with microfluidic hydrogel fabrication, quantitative multiparametric imaging, Discrete Element Method (DEM) simulations, and in vivo experiments to elucidate these connections. First, we quantified the heterogeneous size and stiffness of primary adipocytes, and replicated these properties by fabricating adipocyte-sized polyacrylamide (PAAm) beads with tunable elasticity. Subsequently, we embedded these beads into type I collagen, the primary fibrillar extracellular matrix (ECM) component of breast adipose tissue, to form 3D granular hydrogels mimicking aspects of native adipose tissue architecture. Granular hydrogels embedded with beads demonstrated increased breast cancer cell invasion relative to bead-free controls, an effect that was more pronounced with soft versus stiff beads and correlated with increased collagen fiber alignment and hierarchical organization. In addition, live cell imaging and DEM simulations revealed that soft beads promoted invasion relative to stiff beads by deforming in response to confined cancer cell migration. Fiber alignment and adipocyte deformation trends were validated in vivo via intravital imaging of cancer cell migration in mammary fat pads of mice, and suggest that adipocyte mechanics regulate breast cancer invasion by coordinating both ECM architecture and cellular confinement. Ultimately, this work highlights the utility of tunable PAAm bead-collagen composites as micromechanical models to study the effect of adipose tissue structure on cancer cell invasion. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/684224v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@d3ce0org.highwire.dtl.DTLVardef@117abb1org.highwire.dtl.DTLVardef@10917faorg.highwire.dtl.DTLVardef@55f3e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Polyacrylamide bead granular hydrogels recapitulate adipose tissue structure and alter cancer cell invasion in a stiffness-dependent manner. The invasion of primary breast cancer cells through mammary adipose is influenced by the heterogeneous mechanical properties of native stromal components, namely adipocytes and extracellular matrix (left). Customizable granular hydrogels provide insight into the physical regulation of breast cancer progression by mimicking adipose tissue extracellular matrix structure (collagen I, i.) and stromal cell mechanics (polyacrylamide bead, ii.), whereby the inclusion of soft beads and/or dilute matrix promotes cancer cell migration compared to stiffer hydrogels (right). C_FIG

bioengineering↗

bioRxiv2025

Label-free Tracking of Subcortical White Matter Degradation In Vivo Using Third Harmonic Generation Microscopy in a Mouse Model of Multiple Sclerosis

Early detection and characterization of myelin degradation in the white matter (WM) is important for understanding neurodegenerative diseases such as multiple sclerosis (MS) and dementia. Here, we demonstrate a label-free in vivo imaging technique using third harmonic generation (THG) microscopy at 1320-nm excitation, which enables visualization of subcellular myelin structural changes deep in the mouse brain. By applying longitudinal THG imaging of the same axons in the cuprizone mouse model of MS, we captured the formation, evolution, and regression of myelin blisters in the corpus callosum through intact cortex - a depth inaccessible to other optical methods. We also confirmed the utility of conducting THG imaging in parallel with three-photon excited fluorescence imaging, which allowed us to determine that myelin blistering events were not correlated with the location of microglia cell bodies. Further, we used post-mortem immunohistochemistry to establish the ability to identify and measure the intranodal distance at nodes of Ranvier using in vivo THG imaging, and we found increased intranodal distances after cuprizone administration. We also developed a novel quantitative metric based on spatial concentration of the brightest THG signal that occurs before more overt changes like myelin blistering. Overall, THG microscopy offers a powerful method for detailed tracking of subcortical myelin dynamics, providing new opportunities to investigate disease mechanisms and potential therapeutic interventions in MS and other neurodegenerative diseases.

bioengineering↗

bioRxiv2025

Psilocybin Prolongs the Neurovascular Coupling Response in Mouse Visual Cortex

Psilocybin has profound therapeutic potential for various mental health disorders, but its mechanisms of action are unknown. Functional MRI studies have reported the effects of psilocybin on brain activity and connectivity; however, these measurements rely on neurovascular coupling to infer neural activity changes and assume that blood flow responses to neural activity are not altered by psilocybin. Using two-photon excited fluorescence imaging in the visual cortex of awake mice to simultaneously measure neural activity and capillary blood flow dynamics, we found that psilocybin administration prolonged the increase in visual stimulus-evoked capillary blood flow - an effect which was reduced by pretreatment with a 5-HT2AR antagonist - despite not causing changes in the stimulus-evoked neural response. Multi-modal widefield imaging also showed that psilocybin extends the stimulus-evoked vascular responses in surface vessels with no observed effect on the population neural response. Computational simulation with a whole-brain neural mass model showed that prolonged neurovascular coupling responses can lead to spurious increases in BOLD-based measures of functional connectivity. Together, these findings demonstrate that psilocybin broadens neurovascular responses in the brain and highlights the importance of accounting for these effects when interpreting human neuroimaging data of psychedelic drug action.

neuroscience↗

bioRxiv2025

Neutrophil arrest in myocardial capillaries drives hypoxia and impairs diastolic function in a mouse model of heart failure with preserved ejection fraction

Impairments in myocardial blood flow have been recognized for decades in human patients with and animal models of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms and roles in pathogenesis remain poorly understood. Using intravital cardiac microcopy in a two-hit mouse model of HFpEF that combines high fat diet and inhibition of nitric oxide synthase, we identified an increase in slow or non-flowing neutrophils in capillaries compared to Control mice. In other mouse models of disease (e.g., in the brain of Alzheimers Disease mice), the presence of such stalled neutrophils leads to organ-wide decreases in perfusion and oxygenation. Administration of antibodies against the neutrophil surface protein Ly6G to deplete neutrophils reduced the number of arrested neutrophils in myocardial capillaries, leading to improvements in myocardial hypoxia, diastolic function, and exercise capacity. This study identifies a previously uncharacterized cellular mechanism that explains myocardial blood flow deficits in mouse models of HFpEF, and demonstrates that improving myocardial blood flow improves cardiac function, without necessitating reversal of pathologic remodeling. Restoring myocardial perfusion by decreasing neutrophil arrest in myocardial capillaries may provide a strategy for improving heart function in HFpEF patients in the future.

physiology↗

bioRxiv2023

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy

Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. AAV-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine 2a receptor-cre driver mice resulted in motor freezing when placed in an MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in-vivo using clinically available devices. TeaserA novel magnetogenetics toolbox to regulate neural circuits in-vivo.

neuroscience↗

bioRxiv2023

Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation

Vitiligo is an autoimmune skin disease caused by cutaneous melanocyte loss. Although phototherapy and T cell suppression therapy have been widely used to induce epidermal re-pigmentation, full pigmentation recovery is rarely achieved due to our poor understanding of the cellular and molecular mechanisms governing this process. Here, we identify unique melanocyte stem cell (McSC) epidermal migration rates between male and female mice, which is due to sexually dimorphic cutaneous inflammatory responses generated by ultra-violet B exposure. Using genetically engineered mouse models, and unbiased bulk and single-cell mRNA sequencing approaches, we determine that manipulating the inflammatory response through cyclooxygenase and its downstream prostaglandin product regulates McSC proliferation and epidermal migration in response to UVB exposure. Furthermore, we demonstrate that a combinational therapy that manipulates both macrophages and T cells (or innate and adaptive immunity) significantly promotes epidermal melanocyte re-population. With these findings, we propose a novel therapeutic strategy for repigmentation in patients with depigmentation conditions such as vitiligo.

cell biology↗

bioRxiv2023

Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer's disease

INTRODUCTIONIn this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODSWe inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTSWe found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSIONOxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

neuroscience↗

bioRxiv2023

A multivariate network analysis of ring- and diffuse-porous tree xylem vasculature segmented by convolutional neural networks

The xylem network, the water conduction system in wood determines the ability of trees to avoid hydraulic failure during drought stress. The capability to withstand embolisms, disruptions of the water column by gas bubbles that contribute to hydraulic failure, is mainly determined by the anatomical arrangement and connectedness (topology) of xylem vessels. However, the quantification of xylem network characteristics has been difficult, so that relating network properties and topology to hydraulic vulnerability and predicting xylem function remains challenging. We studied the xylem vessel networks of three diffuse- (Fagus sylvatica, Liriodendron tulipifera, Populus x canadensis) and three ring-porous (Carya ovata, Fraxinus pennsylvatica, Quercus montana) tree species using volumetric images of xylem from laser ablation tomography (LATscan). Using convolutional neural networks for image segmentation, we generated three-dimensional, high-resolution maps of xylem vessels, with detailed measurements of morphology and topology. We studied the network topologies by incorporating multiple network metrics into a multidimensional analysis and simulated the robustness of these networks against the loss of individual vessel elements that mimic the obstruction of water flow from embolisms. This analysis suggested that networks in Populus x canadensis and Carya ovata are quite similar despite being different wood types. Similar networks had comparable experimental measurements of P50 values (pressure inducing 50% hydraulic conductivity loss) obtained from hydraulic vulnerability curves, a common tool to quantify the cavitation resistance of xylem networks. This work produced novel data on plant xylem vessel networks and introduces new methods for analyzing the biological impact of these network structures. Significance statementThe resilience of fluid transport networks such as xylem vessels that conduct water in trees depends on both the structure of the network and features of the individual network elements. High-resolution reconstruction of xylem networks from six tree species provided novel, three-dimensional, structural data which enabled the xylem networks to be described using graph theory. Using an array of network metrics as multidimensional descriptors, we compared the xylem networks between species and showed relationships to simulated and experimental measures of drought resistance. In addition to providing insight on drought resistance, these approaches offer new ways for comparative analysis of networks applicable to many systems.

plant biology↗

bioRxiv2022

Engineered retrovirus-like Arc extracellular vesicles for the in vivo targeted delivery of mRNA into the brain

Systemic delivery of mRNAs into disease neurons is first limited by the blood-brain-barrier (BBB). Leukocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, emerging as promising carriers to target the disease brain. However, efficient mRNA loading into EVs and their uptake by neurons remain challenges. Here we incorporated inside EVs the endogenous retrovirus-like Arc protein capsids, stabilized by Arc 5UTR RNA elements, to effectively load and deliver mRNAs. Produced from self-derived leukocytes, engineered retrotransposon Arc EVs (eraEVs) are immunologically inert with minimal clearance. Equipped with endothelial adhesion molecules from donor leukocytes, circulating eraEVs enter the brain enriching at neuro-inflammatory sites. During self-assembly, Arc recruits enveloping proteins onto eraEVs further promoting neuronal uptake. Possessing high effectiveness like viral vectors and biocompatibility as natural vesicles, eraEV-nanocarriers can be produced from virtually all donor cell types, potentially leading to the development of future clinical therapies for a range of diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/518870v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@260a4aorg.highwire.dtl.DTLVardef@16da754org.highwire.dtl.DTLVardef@4a79dorg.highwire.dtl.DTLVardef@1983da8_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Circumscribing laser cuts attenuate seizure propagation in a mouse model of focal epilepsy

In partial onset epilepsy, seizures arise focally in the brain and often propagate, causing acute behavior changes, chronic cognitive decline, and increased mortality. Patients frequently become refractory to medical management, leaving neurosurgical resection of the seizure focus as a primary treatment, which can cause neurologic deficits. In the cortex, focal seizures are thought to spread through horizontal connections in layers II/III, suggesting that selectively severing these connections could block seizure propagation while preserving normal columnar circuitry and function. We induced focal neocortical epilepsy in mice and used tightly-focused femtosecond-duration laser pulses to create a sub-surface, opencylinder cut surrounding the seizure focus and severing cortical layers II-IV. We monitored seizure propagation using electrophysiological recordings at the seizure focus and at distant electrodes for 3-8 months. With laser cuts, only 5% of seizures propagated to the distant electrodes, compared to 85% in control animals. Laser cuts also decreased the number of seizures that were initiated, so that the average number of propagated seizures per day decreased from 42 in control mice to 1.5 with laser cuts. Physiologically, these cuts produced a modest decrease in cortical blood flow that recovered within days and, at one month, left a ~20-m wide scar with increased gliosis and localized inflammatory cell infiltration but minimal collateral damage. When placed over motor cortex, cuts did not cause notable deficits in a skilled reaching task. Femtosecond laser produced sub-surface cuts hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy, as might develop following traumatic brain injury. Once sentence summaryIn a mouse model of focal epilepsy, sub-surface laser-produced cuts encircling the seizure focus attenuate propagation without behavioral impairment.

neuroscience↗

bioRxiv2021

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimers disease mouse model

Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimers disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.

neuroscience↗

bioRxiv2021

Genetically Engineered Strains for Combinatorial Cardiovascular Optobiology

Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage -specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3 (opto1AR) and cAMP (opto{beta}2AR), or Ca2+- permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+ imaging in HCN4BAC-CatCh2/MHC-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks.

physiology↗

bioRxiv2019

High fat diet worsens pathology and impairment in an Alzheimers mouse model, but not by synergistically decreasing cerebral blood flow

Obesity is linked to increased risk for and severity of Alzheimers disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We showed that non-flowing capillaries, caused by adhered neutrophils, underlie the CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd. Significance statementObesity, especially in mid-life, has been linked to increased risk for and severity of Alzheimers disease. Here, we show that blocking adhesion of white blood cells leads to increases in brain blood flow that improve cognitive function, regardless of whether mice are obese or not.

neuroscience↗

bioRxiv2018

Aspirin treatment does not increase microhemorrhage size in young or aged mice

Microhemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimers disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2-5 months old) and aged (18-29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) m in controls and 109 +/- 25 (101 +/- 28) m in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 m. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.

neuroscience↗