Biology subjects

McQuaid, C.

Publications and source records attributed to McQuaid, C..

4 recordsLinked to original sources

bioRxiv2026

Pericyte Loss Reprogrammes Capillary Endothelium and Drives White Matter Injury in Small Vessel Disease

Pericytes are critical regulators of cerebrovascular homeostasis, yet their contribution to small vessel disease (SVD) and white matter injury remains incompletely understood. Here, we use an inducible Atp13a5-driven genetic strategy to selectively label and ablate brain pericytes, enabling integrated morphological, functional, and transcriptomic analyses across the neurogliovascular unit. Single-cell RNA sequencing and tissue-level mapping identified distinct pericyte subtypes distributed along the vascular tree and revealed subtype-specific vulnerability following depletion. Moderate pericyte loss induced transient cerebrovascular dysfunction characterised by reduced cerebral blood flow and increased blood-brain barrier (BBB) permeability, accompanied by delayed white matter abnormalities, including altered diffusion MRI metrics, oligodendrocyte progenitor cell responses, and myelin loss. At the molecular level, pericyte depletion reprogrammed capillary endothelial cells toward an activated venular-like state characterised by VCAM-1 induction, reduced expression of the BBB-associated transporter MFSD2A, and activation of type I interferon signalling pathways. Cross-species analyses revealed enrichment of human white matter hyperintensity-associated SVD gene signatures across endothelial subtypes following pericyte depletion. Together, these findings identify pericyte dysfunction as a driver of endothelial inflammatory remodelling and white matter injury and establish mechanistic links between microvascular pericyte loss and human SVD.

neuroscience↗

bioRxiv2026

Abrupt Pericyte Loss Precedes Endothelial Activation in Cerebral Small Vessel Disease

Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular cognitive impairment, yet the cellular mechanisms underlying microvascular dysfunction in human disease remain incompletely understood. In particular, the relationship between pericyte alterations and endothelial activation, two key features of blood-brain barrier dysfunction, remains unresolved. Here, we performed a quantitative single-vessel analysis of the human cortical microvasculature across increasing cSVD severity and ageing. Using multiplex immunohistochemistry combined with spectral unmixing and automated image analysis, we analysed 11,409 microvascular fragments from post-mortem brain tissue derived from 20 cases. Endothelial cells, pericytes, and endothelial activation were assessed using PECAM-1, PDGFR{beta}, and VCAM-1, respectively. Microvascular density and diameter differed between cortical grey matter and the underlying white matter, with white matter vessels being less dense and wider in controls. While vessel diameter remained stable across disease stages, microvascular density increased with cSVD severity and age in the white matter. At the molecular level, PDGFR{beta} signal decreased markedly with increasing cSVD severity, consistent with progressive pericyte loss. This reduction was observed in both grey and white matter and correlated with disease severity and age. Notably, intermediate disease groups displayed marked heterogeneity, with vessels exhibiting either preserved or near-complete pericyte coverage, suggesting a potentially bimodal transition. In parallel, endothelial markers PECAM-1 and VCAM-1 increased significantly with disease severity, reflecting endothelial activation. Unsupervised Gaussian mixture clustering of marker expression identified three vascular states characterised by (i) preserved pericytes with low endothelial activation, (ii) marked pericyte loss without endothelial activation, and (iii) combined pericyte depletion and endothelial activation. These clusters broadly aligned with clinical severity but revealed intermediate states not captured by post-mortem diagnosis alone. Together, these findings suggest that pericyte loss and endothelial activation are partially dissociated processes that occur in a sequential progression in human cSVD, supporting pericyte dysfunction as an early event and highlighting it as a potential therapeutic target in microvascular disease.

pathology↗

bioRxiv2022

SARS-CoV-2 spike proteins uptake mediated by lipid raft ganglioside GM1 in human cerebrovascular cells

While there is clinical evidence of neurological manifestation in coronavirus disease-19, its unclear whether this is due to differential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake from blood by cells of the cerebrovasculature. SARS-CoV-2 and its spike protein (SP) interact with the endothelium but the roles of extracellular peptidase domain on angiotensin converting enzyme 2 receptors (ACE2) and ACE2 independent pathways (such as glycans) are not fully elucidated. In addition, for SARS-CoV-2 to enter the brain parenchyma from blood it has to cross several cell types, including the endothelium, pericytes and vascular smooth muscle. Since SARS-CoV-2 interacts with host cells via it SP at the entry point of it life cycle, we used fluorescently labelled SP (SP-555) (wild type and mutants) to model viral behaviour, in vitro, for these cell types (endothelial, pericytes and vascular smooth muscle) to explore pathways of viral entry into brain from blood. There was differential SP uptake by these cell types. The endothelial cells had the least uptake, which may limit SP uptake into brain from blood. Uptake was mediated by ACE2, but it was dependent on SP interaction with ganglioside GM1 in the lipid raft. Mutation sites, N501Yand E484K and D614G, as seen in variants of interest, were differentially taken up by these cell types. There was greater uptake but neutralization with anti-ACE2 and anti-GM1antibodies was less effective. Our data suggested that GM1/lipid raft is an important entry point of SARS-CoV-2 into these cells since inhibition of SP uptake with both anti-ACE2 and anti-GM1 together was similar to that with only anti-GM1, and both ACE2 and GM1 are within the lipid raft region of plasma membrane. Thus, GM1 is a potential SARS-CoV-2 and therapeutic target at the cerebrovasculature.

neuroscience↗

bioRxiv2021

Spike protein multiorgan tropism suppressed by antibodies targeting SARS-CoV-2

While there is clinical evidence of severe acute respiratory syndrome coronavirus 2 multiorgan tropism in severely infected coronavirus 19 patients, its unclear if there is differential multiorgan biodistribution and organ uptake in healthy young individuals, a group that usually has asymptomatic to moderate coronavirus 19 symptoms. In addition, for antibody therapies and vaccines that target the spike protein, its unclear if these reduce severe acute respiratory syndrome coronavirus 2 or spike protein multiorgan tropism equally. We used fluorescently labeled spike protein near infrared fluorescence to study viral behavior, using an in vivo dynamic imaging system, in young mice. We found a spike protein body-wide biodistribution followed by a slow regional elimination, except for the liver, which showed an accumulation. Spike protein uptake was highest for the lungs, and this was followed by kidney, heart and liver, but, unlike the choroid plexus, it was not detected in the brain parenchyma or cerebrospinal fluid. Thus, the brain vascular barriers were effective in restricting the entry of spike protein into brain parenchyma in young healthy mice. While both anti-angiotensin converting enzyme 2 and anti-spike protein antibodies suppressed spike protein biodistribution and organ uptake, anti-spike protein antibody was more effective. By extension, our data support the efficacy of these antibodies on severe acute respiratory syndrome coronavirus 2 biodistribution kinetics and multiorgan tropism that could determine coronavirus 19 organ-specific outcomes.

neuroscience↗