Biology subjects

Browning, J. L.

Publications and source records attributed to Browning, J. L..

4 recordsLinked to original sources

bioRxiv2025

Vascular amyloidβ load in the meningeal arterial network correlates with loss of cerebral blood flow and pial collateral vessel enlargement in the J20 murine model of Alzheimer's disease

BackgroundGlobal reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimers disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network--a critical supplier of intracortical perfusion--has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD. MethodsUsing premortem delivery of Methoxy-XO4 to label A{beta}, and arterial vascular labeling, we assessed A{beta} burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice. ResultsWe show that 12-month-old J20 mice exhibit significant A{beta} deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with [~]40% vessel coverage in males and [~]20% in females--substantially exceeding A{beta} levels in cortical or hippocampal vessels. This vascular A{beta} burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by [~]15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden. ConclusionsThis is the first study to comprehensively characterize meningeal arterial A{beta} accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal A{beta} pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.

neuroscience↗

bioRxiv2024

Astrocyte TrkB.T1 deficiency disrupts glutamatergic synaptogenesis and astrocyte-synapse interactions.

Perisynaptic astrocyte processes (PAPs) contact pre- and post-synaptic elements to provide structural and functional support to synapses. Accumulating research demonstrates that the cradling of synapses by PAPs is critical for synapse formation, stabilization, and plasticity. The specific signaling pathways that govern these astrocyte-synapse interactions, however, remain to be elucidated. Herein, we demonstrate a role for the astrocyte TrkB.T1 receptor, a truncated isoform of the canonical receptor for brain derived neurotrophic factor (BDNF), in modulating astrocyte-synapse interactions and excitatory synapse development. Neuron-astrocyte co-culture studies revealed that loss of astrocyte TrkB.T1 disrupts the formation of PAPs. To elucidate the role of TrkB.T1 in synapse development, we conditionally deleted TrkB.T1 in astrocytes in mice. Synaptosome preparations were employed to probe for TrkB.T1 localization at the PAP, and confocal three-dimensional microscopy revealed a significant reduction in synapse density and astrocyte-synapse interactions across development in the absence of astrocytic TrkB.T1. These findings suggest that BDNF/TrkB.T1 signaling in astrocytes is critical for normal excitatory synapse formation in the cortex and that astrocyte TrkB.T1 serves a requisite role in astrocyte synapse interactions. Overall, this work provides new insights into the molecular mechanisms of astrocyte-mediated synaptogenesis and may have implications for understanding neurodevelopmental disorders and developing potential therapeutic targets.

neuroscience↗

bioRxiv2023

Infection-induced epilepsy is caused by increased expression of chondroitin sulfate proteoglycans in hippocampus and amygdala

Alterations in the extracellular matrix (ECM) are common in epilepsy, yet whether they are cause or consequence of disease is unknow. Using Theilers virus infection model of acquired epilepsy we find de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was normalized by aggrecan deletion. In situ experiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations (K+, Ca2+) on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. We show similar changes in CSPGs in pilocarpine-induced epilepsy suggesting enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and novel therapeutic potential.

neuroscience↗

bioRxiv2023

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive multiorgan fibrosis. While the cause of SSc remains unknown, a perturbed vasculature is considered a critical early step in the pathogenesis. Using fibrinogen as a marker of vascular leakage, we found extensive extravascular fibrinogen deposition in the dermis of both limited and diffuse systemic sclerosis disease, and it was present in both early and late-stage patients. Based on a timed series of excision wounds, retention on the fibrin deposit of the splice variant domain, fibrinogen EC, indicated a recent event, while fibrin networks lacking the EC domain were older. Application of this timing tool to SSc revealed considerable heterogeneity in EC domain distribution providing unique insight into disease activity. Intriguingly, the fibrinogen-EC domain also accumulated in macrophages. These observations indicate that systemic sclerosis is characterized by ongoing vascular leakage resulting in extensive interstitial fibrin deposition that is either continually replenished and/or there is impaired fibrin clearance. Unresolved fibrin deposition might then incite chronic tissue remodeling.

pathology↗