Reactive astrocytes associated with prion disease impair the blood brain barrier

Abstract

Background. Impairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinso'n s and prion diseases. In prion disease, increased BBB permeability was reported 40 years ago, yet the mechanisms behind the loss of BBB integrity have never been explored. Recently, we showed that reactive astrocytes associated with prion diseases are neurotoxic. The current work examines the potential link between astrocyte reactivity and BBB breakdown. Results. In prion-infected mice, the loss of BBB integrity and aberrant localization of aquaporin 4 (AQP4), a sign of retraction of astrocytic endfeet from blood vessels, were noticeable prior to disease onset. Gaps in cell-to-cell junctions along blood vessels, together with downregulation of Occludin, Claudin-5 and VE-cadherin, which constitute tight and adherens junctions, suggested that loss of BBB integrity is linked with degeneration of vascular endothelial cells. In contrast to cells isolated from non-infected adult mice, endothelial cells originating from prion-infected mice displayed disease-associated changes, including lower levels of Occludin, Claudin-5 and VE-cadherin expression, impaired tight and adherens junctions, and reduced trans-endothelial electrical resistance (TEER). Endothelial cells isolated from non-infected mice, when co-cultured with reactive astrocytes isolated from prion-infected animals or treated with media conditioned by the reactive astrocytes, developed the disease-associated phenotype observed in the endothelial cells from prion-infected mice. Reactive astrocytes were found to produce high levels of secreted IL-6, and treatment of endothelial monolayers originating from non-infected animals with recombinant IL-6 alone reduced their TEER. Remarkably, treatment with extracellular vesicles produced by normal astrocytes partially reversed the disease phenotype of endothelial cells isolated from prion-infected animals. Conclusions. To our knowledge, the current work is the first to illustrate early BBB breakdown in prion disease and to document that reactive astrocytes associated with prion disease are detrimental to BBB integrity. Moreover, our findings suggest that the harmful effects are linked to proinflammatory factors secreted by reactive astrocytes.

Interactions between Cytokines and the Pathogenesis of Prion Diseases: Insights and Implications

“…Interestingly, this compromise in barrier integrity could be attributed to high levels of IL-6 secreted by reactive astrocytes. Such an increase in IL-6 was observed to reduce the levels of TJ proteins in non-infected mice-isolated endothelial cells within a co-culture model [27], although IL-6 itself is not directly linked to prion diseases progression [66]. Also, TNF-α has been shown to promote a decrease in claudin-5 expression in mice-isolated endothelial cells [67], which may suggest that this cytokine contributes to BBB dysfunction in TSEs when released by activated microglia in response to PrPSc [22].…”

“…Recent studies have demonstrated that in prion-infected mice, the integrity of the BBB is compromised prior to the manifestation of clinical symptoms [27]. Furthermore, endothelial cells isolated from these mice exhibit reduced levels of the tight junction proteins occluding and claudin-5, as well as the adherens junction protein VE-cadherin [27]. Interestingly, this compromise in barrier integrity could be attributed to high levels of IL-6 secreted by reactive astrocytes.…”

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

“…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). Increased expression and depolarized subcellular distribution of AQP4 has been shown in animal models of neuroinflammation and neurodegeneration such as traumatic brain injury (Ren et al, 2013), local ischemia (Wang et al, 2012), edema (Tourdias et al, 2011), prion disease (Kushwaha et al, 2023) and Alzheimer's disease (Feng et al, 2023;Pedersen, Keil, Han, Wang, & Iliff, 2023;J. Yang et al, 2011).…”