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Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology.

ABSTRACT: HIV-infected brains are characterized by increased amyloid beta (A?) deposition. It is believed that the blood-brain barrier (BBB) is critical for A? homeostasis and contributes to A? accumulation in the brain. Extracellular vesicles (ECV), like exosomes, recently gained a lot of attention as potentially playing a significant role in A? pathology. In addition, HIV-1 hijacks the exosomal pathway for budding and release. Therefore, we investigated the involvement of BBB-derived ECV in the HIV-1-induced A? pathology in the brain. Our results indicate that HIV-1 increases ECV release from brain endothelial cells as well as elevates their A? cargo when compared to controls. Interestingly, brain endothelial cell-derived ECV transferred A? to astrocytes and pericytes. Infusion of brain endothelial ECV carrying fluorescent A? into the internal carotid artery of mice resulted in A? fluorescence associated with brain microvessels and in the brain parenchyma. These results suggest that ECV carrying A? can be successfully transferred across the BBB into the brain. Based on these observations, we conclude that HIV-1 facilitates the shedding of brain endothelial ECV carrying A?; a process that may increase A? exposure of cells of neurovascular unit, and contribute to amyloid deposition in HIV-infected brain.

SUBMITTER: Andras IE

PROVIDER: S-EPMC5315639 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology.

András Ibolya E IE Leda Ana A Contreras Marta Garcia MG Bertrand Luc L Park Minseon M Skowronska Marta M Toborek Michal M

Molecular and cellular neurosciences 20161229

HIV-infected brains are characterized by increased amyloid beta (Aβ) deposition. It is believed that the blood-brain barrier (BBB) is critical for Aβ homeostasis and contributes to Aβ accumulation in the brain. Extracellular vesicles (ECV), like exosomes, recently gained a lot of attention as potentially playing a significant role in Aβ pathology. In addition, HIV-1 hijacks the exosomal pathway for budding and release. Therefore, we investigated the involvement of BBB-derived ECV in the HIV-1-in ...[more]

PMID: 28040512

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Project description:BackgroundPICALM is one of the most significant susceptibility factors for Alzheimer's disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology.MethodsTo identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm+/-) mice, Picalm+/-; 5XFAD mice and Picalmlox/lox; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior.ResultsOur screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm+/- mice by 2-3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm+/-; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34-51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm+/-; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects.ConclusionsArtesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.

Dataset Information

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology.

Publications

Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology.

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