The most significant development in HIV epidemiology is the increasing age in the infected population. Among HIV-associated comorbidities that have been related to aging, neurocognitive dysfunction and vascular disorders are particularly striking. The current proposal links both conditions together by focusing on the blood-brain barrier (BBB) and neurogenesis of neural progenitor cells (NPC). HIV infected brains are characterized by increased deposition of amyloid beta (A?), and we demonstrated in the previous funding cycle that the BBB (formed primarily by the endothelium of brain capillaries) actively participates in this process. The current proposal will explore the role of the brain endothelium-derived extracellular vesicles (ECV) in A? transfer to neural progenitor cells (NPC) and their impaired neurogenesis in HIV-infected brains. The proposed research is built on the notion that enhanced accumulation of A?, toxicity of anti-retroviral therapeutics, and residual viral replication in HIV-infected brain are driving the brain pathology resulting in neurocognitive decline. The central hypothesis of the proposal is that A? carried by ECV derived from the brain endothelium enhances HIV infection of NPC and impairs their differentiation into the neuronal lineage, resulting in neurocognitive decline. Specific mechanisms evaluated in this application include the impact of A? carried by the brain endothelium-derived ECV on HIV infection and the impaired neurogenesis of NPC (Aim 1), alterations of gap junction-mediated intercellular communication between infected and non-infected NPC (Aim 2), and (Aim 3) the contribution of anti-retroviral drugs to amyloid deposition and impaired neurogenesis of NPC in HIV-infected brain. Overall, the proposal offers a unique perspective on the interactions between the BBB and A? deposits in a HIV-infected brain, resulting in impaired NPC neurogenesis. We expect that the project will provide proof-of-principle for the involvement of A? in the development of cognitive dysfunction in HIV.
Increased deposition of amyloid beta (A?) is a feature of normal aging, which is markedly enhanced in the brains infected by HIV. The central hypothesis of this proposal is that A? carried by extracellular vesicles (ECV) derived from the brain endothelium enhances HIV infection of neural progenitor cell and impairs their differentiation into the neuronal lineage, resulting in neurocognitive decline. Overall, the proposal offers a unique perspective on the interactions between the blood-brain barrier (BBB) and A? deposits in a HIV- infected brain, resulting in impaired NPC neurogenesis.
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|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|
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|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 :|
|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|
|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|
|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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