Biology subjects

Woltjer, R.

Publications and source records attributed to Woltjer, R..

5 recordsLinked to original sources

bioRxiv2026

APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice

Old age and the apolipoprotein E {varepsilon}4 (APOE4) genotype are two of the greatest risk factors for late-onset Alzheimers disease (LOAD). However, the interaction between these is poorly understood, as most preclinical studies use young mice. Therefore, we assessed the interaction between APOE genotype and age across a comprehensive set of cerebrovascular and related outcomes. We performed in vivo imaging, ex vivo cerebral artery studies, behavioral tests, and molecular analyses in male and female homozygous APOE3 and APOE4 mice at [~]6 months (young) and [~]24 months (old). APOE4 interacted with old age to lead to deficits in brain volume and greater microglia content. Old APOE4 mice also exhibited greater cerebral artery vasoconstriction to endothelin-1 (ET-1) than old APOE3 mice, a response concomitant with age-and genotype-related differences in the expression of ET-1 receptors and endothelin-converting enzyme. While we found several interactions between age and APOE genotype, only age impacted cognitive function, cerebral artery endothelial function, and arterial stiffness. In summary, we found that brain volume, neuroinflammation, and ET-1-related outcomes were influenced by the interaction of APOE genotype and age, while other outcomes were affected only by age. As such, an altered ET-1 response and greater neuroinflammation may contribute to the increased risk for LOAD in APOE4 carriers.

neuroscience↗

bioRxiv2026

Medin-Induced Pro-inflammatory and Prothrombotic Activation of Coronary Artery Endothelial Cells: A Potential Novel Mediator Linking Aging and Atherosclerosis

BackgroundAge is the most important risk factor for coronary artery disease (CAD) independent of traditional risk factors. Aging induces classic pro-inflammatory and prothrombotic vascular phenotypic changes whose molecular mediators remain poorly understood. Medin is a common cleavage product protein that accumulates in vasculature with aging and shown to cause endothelial dysfunction. Its role in CAD is unknown. The study aimed to evaluate the effects of medin on human coronary artery endothelial cell (HCAEC) pro-inflammatory and prothrombotic activation and establish the relationship between medin and coronary atherosclerosis in human decedents. MethodsHCAECs were exposed to physiologic dose of medin (5 {micro}M) for 20 hours and ribonucleic acid sequencing (RNAseq) with signaling pathway analyses and reverse transcription polymerase chain reaction of select pro-inflammatory and prothrombotic genes performed. Corresponding protein expression was measured by Western blot or enzyme linked immunosorbent assay in HCAECs exposed to medin (5 {micro}M) without or with nuclear factor-{kappa}B (NF{kappa}B) inhibitor RO106-9920 (10 {micro}M). Coronary arteries from 40 deceased individuals underwent immunohistochemistry and medin and plaque burden were quantified and their relationship evaluated. ResultsRNAseq showed predominant pro-inflammatory gene expression changes induced by medin. HCAECs treated with medin showed increased phosphorylated NF{kappa}B, elevated protein expression of interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and plasminogen activator inhibitor (PAI)-1 and reduced protein expression of thrombomodulin; these changes were reversed by RO106-9920 co-treatment. In human tissues, coronary artery medin strongly correlated with plaque burden (R=0.76, p<0.0001) and coronary macrophage content (R=0.72, p<0.0001). Coronary arteries from decedents with myocardial infarction had higher medin than those without (5.53{+/-}2.67% versus 0.02{+/-}0.02%, p=0.0005). ConclusionsMedin induced NF{kappa}B-mediated endothelial cell pro-inflammatory and prothrombotic activation and was strongly associated with coronary plaque burden and inflammation. Medin is a novel candidate mediator linking aging and coronary atherosclerosis.

physiology↗

bioRxiv2025

Mild subcortical stroke induces widespread astrogliosis independent of microglia and age

Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimers disease. The cause of this extensive pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke confined to subcortical regions, similar to most silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, permeating the entire middle cerebral artery territory, compared to the reactive microglial response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent the reactive astrocytes, suggesting that ischemia-driven astrogliosis is largely microglia-independent. Lastly, we show that aging mice exposed to MSCI exhibit a comparably strong response of reactive astrocytes and microglia as young mice. We propose that MSCI is a novel and valuable model for examining the subtle yet highly important chronic effects of stroke. It may be especially useful for investigating the influence of reactive astrogliosis on pathologies like neuroinflammation and cerebrovascular dysfunction in regions distal from the primary injury site.

neuroscience↗

bioRxiv2024

Deletion of Robo4 worsens neuroinflammation and motor coordination in a mouse model of Alzheimer's disease

Declines in vascular integrity are potential contributors to Alzheimers disease (AD) as these result in increased blood-brain barrier permeability and, as a consequence, accelerate neuroinflammation and cognitive impairment. Roundabout guidance receptor 4 (Robo4) is primarily expressed in endothelial cells and stabilizes the vasculature, and thus, has the potential to protect the brain in AD. To study the effect of Robo4 on neuroinflammation and cognitive function in the context of AD, we compared Robo4 knockout and wildtype mice crossed with mice with and without AD mutations (APP/tau). We found that the knockout of Robo4 led to greater astrocyte activation, as demonstrated by GFAP content, but this was dependent on the brain region studied. The knockout of Robo4 also led to greater activated microglia, as assessed by Iba1 content, but only in the presence of AD-related mutations. We found that AD mutations, but not Robo4, were associated with cognitive dysfunction measured by a nest-building test. In contrast, Robo4 deletion, but not AD mutations, was associated with impaired motor coordination. Lastly, Robo4 deletion was associated with greater arterial stiffness, but this trend did not reach statistical significance. In summary, these results demonstrate that Robo4 impacts neuroinflammation, motor coordination, and arterial stiffness, however, the impact on neuroinflammation is dependent on the presence/absence of AD-related mutations and the brain region examined.

physiology↗

bioRxiv2021

GPR39 Localization in Aging Human Brain and Correlation of Expression and Polymorphism with Vascular Cognitive Impairment

INTRODUCTIONThe pathogenesis of vascular cognitive impairment (VCI) is not fully understood. GPR39, an orphan G-protein coupled receptor, is implicated in neurological disorders but its role in VCI is unknown. METHODSWe performed GPR39 immunohistochemical analysis in postmortem brain samples from mild cognitive impairment (MCI) and control subjects. DNA was analyzed for GPR39 SNPs, and correlated with white matter hyperintensity (WMH) burden on premortem MRI. RESULTSGPR39 is expressed in aged human dorsolateral prefrontal cortex, localized to microglia and peri-capillary cells resembling pericytes. GPR39-capillary colocalization, and density of GPR39-expressing microglia was increased in aged brains compared to young. SNP distribution was equivalent between groups; however, homozygous SNP carriers were present only in the MCI group, and had higher WMH volume than WT or heterozygous SNP carriers. DISCUSSIONGPR39 may play a role in aging-related VCI, and may serve as a therapeutic target and biomarker for the risk of developing VCI.

neuroscience↗