Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

Min, Zhou; Shi, Samuel; Liu, Ning; Jiang, Yinghua; Karim, Mardeen S.; Vodovoz, Samuel J.; Wang, Xiaoying; Zhang, Boli; Dumont, Aaron S.

doi:10.3390/jcm10173795

Cited by 22 publications

(12 citation statements)

References 62 publications

(96 reference statements)

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“…In contrast, caveolae-mediated transcytosis mediates the blood-to-brain entry of viruses and extracellular proteins such as albumin 34 . Dysregulated caveolae-mediated transcytosis is believed to increase BBB permeability under pathological conditions triggered by ischemic stroke 35 and sub-arachnoid hemorrhage 36 or under exposure to low-intensity focused ultrasound 37 . Therefore, we investigated the involvement of both clathrin and caveolae mediated endocytic mechanisms in Aβ uptake at the BBB endothelium.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Wang

Sharda

Omtri

et al. 2022

Preprint

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Blood-brain barrier (BBB) is a critical portal regulating the bidirectional transport of amyloid beta (Aβ) proteins between blood and brain. Disrupted trafficking at the BBB may not only promote the build-up of Aβ plaques in the brain parenchyma, but also facilitate Aβ accumulation within the BBB endothelium, which aggravates BBB dysfunction. Soluble Aβ42:Aβ40 ratios in plasma and cerebrospinal fluid have been reported to decrease during Alzheimer's disease (AD) progression. Our previous publications demonstrated that trafficking of Aβ42 and Aβ40 at the BBB is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aβ40 and Aβ42 have not been clearly elucidated. In this study, we identified mechanisms of fluorescently labeled Aβ (F-Aβ) endocytosis in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers using pharmacological inhibition and siRNA knock-down approaches. Further, intracellular transit of F-Aβ following endocytosis was tracked using live cell imaging. Our studies demonstrated that both F-Aβ peptides were internalized by BBB endothelial cells via energy, dynamin and actin dependent endocytosis. Interestingly, endocytosis of F-Aβ40 is found to be clathrin-mediated, whereas F-Aβ42 endocytosis is caveolae-mediated. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. While Aβ42 was shown to accumulate more in the lysosome which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aβ40 demonstrated robust accumulation in recycling endosomes which may facilitate its transcytosis across the BBB. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aβ40 versus Aβ42. This knowledge contributes to the understanding of molecular pathways underlying Aβ accumulation in the BBB endothelium and associated cerebrovascular dysfunction as well as amyloid deposition in the brain parenchyma which are implicated in AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Wang

Sharda

Omtri

et al. 2022

Preprint

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“…[79] Plasma-membrane vesicles such as caveolae, loaded with their cargo components, are then transferred from the apical to the basal side of the endothelium. [80] The affinity of adsorption-mediated transcytosis is very low but allows the transport of a large number of molecules compared to RMT. [33] Previously, adsorption-mediated transcytosis was assessed in BBB-on-a-chip by measuring the permeability to albumin.…”

Section: Transport Pathwaysmentioning

confidence: 99%

Organ‐On‐A‐Chip Models of the Blood–Brain Barrier: Recent Advances and Future Prospects

Kawakita

Mandal

Mou

et al. 2022

Small

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refers to a multicellular unit in the brain including cells of the cerebral vasculature and brain parenchyma. [2] As part of the NVU, the blood-brain barrier (BBB) acts as a physiological barrier at the interface between peripheral blood circulation and the central nervous system (CNS). The BBB is indispensable for the proper CNS function and regulation of CNS homeostasis; it controls the transport of substances between the CNS and the blood via various transport mechanisms. [3] The BBB also protects the brain from neurotoxic plasma components, certain chemicals, and pathogens. Functional and structural changes of the BBB are implicated in several neurological diseases and disorders, which have severely impacted individuals worldwide. For example, there are currently estimated to be about 5.7 million people living with Alzheimer's disease (AD), and the number is projected to reach 13.8 million by 2050. [4] Stroke is the second leading cause of death and the third most common cause of disability. [5] Glioblastoma multiforme (GBM), which accounts for almost 50% of all brain tumors (i.e., glioma), is relatively rare with a global incidence rate of 3.19 per 100 000 people; however, it has a devastatingly poor prognosis with a typical survival rate of 14-15 months rendering it a critical public health problem. [6] The human brain and central nervous system (CNS) present unique challenges in drug development for neurological diseases. One major obstacle is the blood-brain barrier (BBB), which hampers the effective delivery of therapeutic molecules into the brain while protecting it from blood-born neurotoxic substances and maintaining CNS homeostasis. For BBB research, traditional in vitro models rely upon Petri dishes or Transwell systems. However, these static models lack essential microenvironmental factors such as shear stress and proper cell-cell interactions. To this end, organ-on-a-chip (OoC) technology has emerged as a new in vitro modeling approach to better recapitulate the highly dynamic in vivo human brain microenvironment socalled the neural vascular unit (NVU). Such BBB-on-a-chip models have made substantial progress over the last decade, and concurrently there has been increasing interest in modeling various neurological diseases such as Alzheimer's disease and Parkinson's disease using OoC technology. In addition, with recent advances in other scientific technologies, several new opportunities to improve the BBB-on-a-chip platform via multidisciplinary approaches are available. In this review, an overview of the NVU and OoC technology is provided, recent progress and applications of BBB-on-a-chip for personalized medicine and drug discovery are discussed, and current challenges and future directions are delineated.The ORCID identification number(s) for the author(s) of this article can be found under

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“…The resulting endothelial cell dysfunction involves the production of reactive oxygen metabolites, swelling, or detachment from the underlying basement membrane, and compromised barrier function leading to increased protein extravasation and interstitial edema [40,41]. These events generally occur in post-capillary segments of the microvasculature and are often accompanied by the adhesion of leukocytes.…”

Section: T-cell-mediated Endothelial and Nvu Dysfunctionmentioning

confidence: 99%

T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage

Shi

Vodovoz

Xiu

et al. 2022

Cells

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In the pathophysiology of hemorrhagic stroke, the perturbation of the neurovascular unit (NVU), a functional group of the microvascular and brain intrinsic cellular components, is implicated in the progression of secondary injury and partially informs the ultimate patient outcome. Given the broad NVU functions in maintaining healthy brain homeostasis through its maintenance of nutrients and energy substrates, partitioning central and peripheral immune components, and expulsion of protein and metabolic waste, intracerebral hemorrhage (ICH)-induced dysregulation of the NVU directly contributes to numerous destructive processes in the post-stroke sequelae. In ICH, the damaged NVU precipitates the emergence and evolution of perihematomal edema as well as the breakdown of the blood–brain barrier structural coherence and function, which are critical facets during secondary ICH injury. As a gateway to the central nervous system, the NVU is among the first components to interact with the peripheral immune cells mobilized toward the injured brain. The release of signaling molecules and direct cellular contact between NVU cells and infiltrating leukocytes is a factor in the dysregulation of NVU functions and further adds to the acute neuroinflammatory environment of the ICH brain. Thus, the interactions between the NVU and immune cells, and their reverberating consequences, are an area of increasing research interest for understanding the complex pathophysiology of post-stroke injury. This review focuses on the interactions of T-lymphocytes, a major cell of the adaptive immunity with expansive effector function, with the NVU in the context of ICH. In cataloging the relevant clinical and experimental studies highlighting the synergistic actions of T-lymphocytes and the NVU in ICH injury, this review aimed to feature emergent knowledge of T cells in the hemorrhagic brain and their diverse involvement with the neurovascular unit in this disease.

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Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

Cited by 22 publications

References 62 publications

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Organ‐On‐A‐Chip Models of the Blood–Brain Barrier: Recent Advances and Future Prospects

T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage

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