for update 12

Ibolya’s study on the impact of HIV-1 and amyloid beta on remodleing proteome of brain endothelial extracellular vesicles has been published in the International Journal of Molecular Sciences 

Congratulations Ibolya!!

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles Ibolya E. András, Brice Sewell, and Michal Toborek Int J Mol Sci 21, 2741, 2020

Abstract

Amyloid beta (Aβ) depositions are more abundant in HIV-infected brains. The blood-brain barrier, with its backbone created by endothelial cells, is assumed to be a core player in Aβ homeostasis and may contribute to Aβ accumulation in the brain. Exposure to HIV increases shedding of extracellular vesicles (EVs) from human brain endothelial cells and alters EV-Aβ levels. EVs carrying various cargo molecules, including a complex set of proteins, can profoundly affect the biology of surrounding neurovascular unit cells. In the current study, we sought to examine how exposure to HIV, alone or together with Aβ, affects the surface and total proteomic landscape of brain endothelial EVs. By using this unbiased approach, we gained an unprecedented, high-resolution insight into these changes. Our data suggest that HIV and Aβ profoundly remodel the proteome of brain endothelial EVs, altering the pathway networks and functional interactions among proteins. These events may contribute to the EV-mediated amyloid pathology in the HIV-infected brain and may be relevant to HIV-1-associated neurocognitive disorders.

April 2020

Ibolya’s study on extracellular vesicle-mediated amyloid transfer to neural progenitor cells has been published in Molecular Brain

Congratulations Ibolya!!

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

Ibolya E. András, Marta Garcia-Contreras, Christopher Yanick, Paola Perez, Brice Sewell, Leonardo Durand, and Michal Toborek

Mol Brain 13, 21, 2020

Abstract

Amyloid beta (Aβ) deposition was demonstrated to be elevated in the brains of HIV-infected patients and associated with neurocognitive decline; however, the mechanisms of these processes are poorly understood. The goal of the current study was to address the hypothesis that Aβ can be transferred via extracellular vesicles (ECVs) from brain endothelial cells to neural progenitor cells (NPCs) and that this process can contribute to abnormal NPC differentiation. Mechanistically, we focused on the role of the receptor for advanced glycation endproducts (RAGE) and activation of the inflammasome in these events. ECVs loaded with Aβ (Aβ-ECVs) were readily taken up by NPCs and Aβ partly colocalized with the inflammasome markers ASC and NLRP3 in the nuclei of the recipient NPCs. This colocalization was affected by HIV and RAGE inhibition by a high-affinity specific inhibitor FPS-ZM1. Blocking RAGE resulted also in an increase in ECV number produced by brain endothelial cells, decreased Aβ content in ECVs, and diminished Aβ-ECVs transfer to NPC nuclei. Interestingly, both Aβ-ECVs and RAGE inhibition altered NPC differentiation. Overall, these data indicate that RAGE inhibition affects brain endothelial ECV release and Aβ-ECVs transfer to NPCs. These events may modulate ECV-mediated amyloid pathology in the HIV-infected brain and contribute to the development of HIV-associated neurocognitive disorders.

February 2020

 

Dr. Silvia Torices received prestigious postdoctoral fellowship from the American Heart Association for her work on “Novel mechanisms of enhanced stroke susceptibility in HIV-infected brain.”

Congratulations Silvia!!!

January 2020

Below is what Allan writes about himself.

I am a transplant from Charlotte, NC. I was welcomed into this great laboratory by Dr. Toborek. While previously I had clinical psychology, cognitive neuroscience, biology and infectious disease coursework, and experience in clinical psychology, cognitive neuroscience/biobehavioral and other biologically oriented laboratories, I felt that this laboratory was a great fit for my main research interests. In the laboratory, also under Dr. Silvia Torices Del Val, in one of the experiments, we are exploring the effects of Occludin on HIV infection, among blood brain barrier cells. I am currently in a biology/infectious disease M.S. degree program. After this laboratory, I intend to pursue a PhD. in Biochemistry, while assessing infectious disease, cell signaling, the blood brain barrier or cognition/mood, and metabolism, for my dissertation. Therefore, I greatly love biology.

Sincerely,

Allan Lewis Kluttz Jr.

B.A. Biology and Psychology

Cognitive Science Graduate Certificate

Prior training in Clinical Psychology (PhD.) / Neuropsychology

R.A.- UM; HIV and Immunological Response at the BBB

M.S. in Infectious Disease (Student) in the College of Medicine

Ana’s study on the impact of Zika virus on the blood-brain barrier has been published in Frontiers of Microbiology

Congratulations Ana!!

Selective Disruption of the Blood-Brain Barrier by Zika Virus

Ana Rachel Leda, Luc Bertrand, Ibolya Edit Andras, Nazira El-Hage, Madhavan Nair, Michal Toborek Front Microbiol 10, 2158, 2019

Abstract

The blood-brain barrier (BBB) selectively regulates the cellular exchange of macromolecules between the circulation and the central nervous system (CNS). Here, we hypothesize that Zika virus (ZIKV) infects the brain via a disrupted BBB and altered expression of tight junction (TJ) proteins, which are structural components of the BBB. To assess this hypothesis, in vitro and in vivo studies were performed using three different strains of ZIKV: Honduras (ZIKV-H), Puerto Rico (ZIKV-PR), and Uganda (ZIKV-U). Primary human brain microvascular endothelial cells (BMECs) were productively infected by all studied ZIKV strains at MOI 0.01, and were analyzed by plaque assay, immunofluorescence for NS1 protein, and qRT-PCR at 2 and 6 days post-infection (dpi). Compared to mock-infected controls, expression level of ZO-1 was significantly upregulated in ZIKV-H-infected BMECs, while occludin and claudin-5 levels were significantly downregulated in BMECs infected by all three studied viral strains. Interestingly, BMEC permeability was not disturbed by ZIKV infection, even in the presence of a very high viral load (MOI 10). All studied ZIKV strains productively infected wild-type C57BL/J mice after intravenous infection with 107 PFU. Viral load was detected in the plasma, spleen, and brain from 1 to 8 dpi. Peak brain infection was observed at 2dpi; therefore, TJ protein expression was assessed at this time point. Claudin-5 was significantly downregulated in ZIKV-U-infected animals and the BBB integrity was significantly disturbed in ZIKV-H-infected animals. Our results suggest that ZIKV penetrates the brain parenchyma early after infection with concurrent alterations of TJ protein expression and disruption of the BBB permeability in a strain-dependent manner.

This paper is the latest of Ana’s excellent contributions to our research program. Unfortunately, Ana left the laboratory for another position. Additional publications by Ana from our laboratory include:

Park MS, Baker W, Cambow D, Gogerty D, Leda AR, Herlihy B, Pavlenko D, Toborek M. Methamphetamine enhances HIV-induced aberrant proliferation of neural progenitor cells via the FOXO3-mediated mechanism. Submitted

Bertrand L, Méroth F, Tournebize M, Leda A, Sun E, Toborek M. Targeting the HIV-infected brain to improve ischemic stroke outcome. Nat Commun 10, 2009, 2019.

Skowronska M, McDonald M, Velichkovska M, Leda AR, Park M, Toborek M. Methamphetamine increases HIV infectivity in neural progenitor cells. J Biol Chem 293, 296-311, 2018.

Leda AR, Dygert L, Bertrand L, Toborek M. Mouse microsurgery infusion technique for targeted substance delivery into the CNS via the internal carotid artery. J Vis Exp 119, 2017.

András IE, Leda A, Garcia Contreras M, Bertrand L, Park M, Skowronska M, Toborek M. Extracellular vesicles of the blood-brain barrier: role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79, 12-22, 2017. An artistic representation of this work (modified figure) was selected for the cover of the journal.

September 2019

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