Subtle vascular and astrocytic changes in the brain of coronavirus disease 2019 (COVID‐19) patients

Abstract

Background and purpose In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic‐ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID‐19) patients. Methods The light microscopy morphology of the vBMs and perivascular astrocytes from brains of 14 patients with confirmed SARS‐CoV‐2 infection was analysed and compared to four control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), tight junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations were calculated, as well as the fractal dimension of astrocytes and vBMs viewed in tangential planes. Results Fractal dimension analysis of the GFAP‐stained astrocytes revealed lower branching complexities and decreased GFAP/collagen IV colocalization for COVID‐19 patients. Interestingly, vBMs showed significantly increased irregularities (fractal dimension values) compared to controls. Vessel diameters were increased in COVID‐19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co‐expression in astrocytes. Conclusions Our data on the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end‐feet and decrease of AQP4 suggest subtle morphological changes of the blood–brain barrier in COVID‐19 brains that could be linked with indirect inflammatory signalling or hypoxia/hypercapnia.

Microgliosis, astrogliosis and loss of aquaporin-4 polarity in frontal cortex of COVID-19 patients

“…In healthy astrocytes, subcellular AQP4 distribution is polarized and AQP4 is mainly located in the astrocyte endfeet surrounding blood vessels, where it functionally contributes to the blood-brain barrier and is involved in extracellular volume dynamics, water homeostasis and waste clearance (Nagelhus & Ottersen, 2013; Rasmussen, Mestre, & Nedergaard, 2022; Verkman, Smith, Phuan, Tradtrantip, & Anderson, 2017). We found increased AQP4 expression and loss of AQP4 polarization in all COVID-19 patients investigated, in contrast to a former study that showed decreased AQP4 (Rosu et al, 2022). Malfunction of AQP4 contributes to the progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, and AQP4 autoantibodies cause neuromyelitis optica spectrum disorder (Buccellato, D’Anca, Serpente, Arighi, & Galimberti, 2022; Mader & Brimberg, 2019; Nedergaard & Goldman, 2020; Pittock, Zekeridou, & Weinshenker, 2021).…”

“…In addition, astrocytes are affected by and are often causal of neurological diseases (Lee, Wheeler, & Quintana, 2022; Lohr, 2023; Patel, Tewari, Chaunsali, & Sontheimer, 2019). In COVID-19, reactive astrogliosis has been reported, including increased expression of glial fibrillary acidic protein (GFAP), and glial markers were found elevated in plasma and cerebrospinal fluid (Hanson et al, 2022; Huang & Fishell, 2022; Kanberg et al, 2020; Rosu et al, 2022; Spanos et al, 2022; Steardo, Steardo, & Scuderi, 2022; Tremblay et al, 2020). In the present study, we investigated the astrocyte markers GFAP, calcium-binding protein S100B and aquaporin-4 (AQP4) as well as microgliosis in frontal lobe of COVID-19 brains using immunohistochemical staining and compared the results with those from control brains.…”

Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice

“…Perivascular cu ng (Fig. 4b) is well described in histological examinations of brains from deceased COVID-19 patients 42,43,66,101,102 . Other lesions observed in the BA.5-infected K18-hACE2 mouse brains, that have also been described in post-mortem COVID-19 patients, include perivascular edema (Fig.…”

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

“…Perivascular cuffing (Fig. 3b) is well described in histological examinations of brains from deceased COVID-19 patients 38,39,56,87,88 . Other lesions observed in the BA.5-infected K18-hACE2 mouse brains, that have also been described in post-mortem COVID-19 patients, include perivascular edema (Fig.…”

“…4D) (Al-Dalahmah et al, 2020; Awogbindin et al, 2021; Matschke et al, 2020; Schwabenland et al, 2021), and occasional small hemorrhagic lesions (Fig. 4E) (Mukerji and Solomon, 2021; Rosu et al, 2022). XBB infected mouse brains showed very similar lesions (Fig.…”