A new element of HIV-1 epidemiology is an increase in the older population infected with HIV-1. This phenomenon is of significant concern because the increasing age may have a detrimental effect on their cognitive functions and facilitate and enhance the development of neurodegenerative diseases in HIV-infected patients. The present application is based on our recent observations that exposure to HIV-1 results in a significant increase in amyloid beta (A2) levels in human brain microvascular endothelial cells. These findings are consistent with strong clinical evidence that indicates increased amyloid deposition in the brain of HIV-1-infected patients. Because blood-borne A2 is the main source of amyloid deposition in the brain, we formed the central hypothesis of the present proposal that HIV-1-induced specific alterations of transporter activities in brain endothelial cells results in intracellular A2 accumulation and its transendothelial passage. We identified that HIV-1-induced activity of the receptor for advanced glycation end products (RAGE) and alterations of ABC efflux transporters (namely, P-glycoprotein [Pgp] and breast cancer resistance protein [BCRP]), may be involved in these processes. It is striking to note that these transporters are associated with cell membrane lipid rafts or their specific subset called caveolae. In addition, expression of these transporters appears to be regulated by small GTPases, such as the Ras and Rho pathways, that are also localized in lipid rafts/caveolae. Therefore, we propose that functional lipid rafts and caveolae provide the signaling platform that is detrimental for HIV-1-induced vascular mechanisms leading to A2 accumulation in the CNS. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation, such as Alzheimer's disease.
We propose that exposure to HIV-1 can increase amyloid beta levels in the CNS by alterations of expression and activity of selected transporters at the level of the blood-brain barrier (BBB). Specifically, we will explore the link between HIV-1-induced alterations of lipid rafts/caveolae-associated signaling, differential regulation of the BBB transporters, and accumulation of amyloid beta in brain endothelial cells, followed by its transendothelial passage. In addition, we will evaluate the protective effects of statins in these events. Data arising from our proposal will be critical for a better understanding of the molecular mechanisms underlying HIV-1-related cerebrovascular injury in older HIV-1-infected individuals. The results generated by the proposed research are also likely to be relevant to other neurodegenerative diseases that have significant cerebrovascular components and are associated with amyloid accumulation, such as Alzheimer's disease.
|Bertrand, Luc; Dygert, Levi; Toborek, Michal (2017) Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J Vis Exp :|
|Cho, Hyung Joon; Kuo, Alyce Mei-Shiuan; Bertrand, Luc et al. (2017) HIV Alters Gap Junction-Mediated Intercellular Communication in Human Brain Pericytes. Front Mol Neurosci 10:410|
|Leda, Ana R; Dygert, Levy; Bertrand, Luc et al. (2017) Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS via the Internal Carotid Artery. J Vis Exp :|
|András, Ibolya E; Leda, Ana; Contreras, Marta Garcia et al. (2017) Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79:12-22|
|Bertrand, Luc; Nair, Madhavan; Toborek, Michal (2016) Solving the Blood-Brain Barrier Challenge for the Effective Treatment of HIV Replication in the Central Nervous System. Curr Pharm Des 22:5477-5486|
|Park, Minseon; Levine, Harry; Toborek, Michal (2016) Exercise protects against methamphetamine-induced aberrant neurogenesis. Sci Rep 6:34111|
|Castro, Victor; Bertrand, Luc; Luethen, Mareen et al. (2016) Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. FASEB J 30:1234-46|
|Bertrand, Luc; Dygert, Levi; Toborek, Michal (2016) Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity. Sci Rep 6:39738|
|Eum, Sung Yong; Jaraki, Dima; András, Ibolya E et al. (2015) Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 287:258-66|
|Bertrand, Luc; Toborek, Michal (2015) Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz. Mol Pharmacol 88:304-15|
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