ABSTRACT
Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV-associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. Blood brain barrier (BBB) dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. In this report, we found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND when compared to HIV-infected patients without DM or seronegative DM patients. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules in primary human brain endothelial cells or human brain pericytes after exposure to HIV and DM-relevant stimuli. Our study demonstrates for the first-time evidence of impaired BBB function in HIV-DM patients and shows potential mechanisms leading to it in brain endothelium and pericytes that may result in poorer cognitive performance compared to individuals without HIV and DM.
Subject(s)
AIDS Arteritis, Central Nervous System/metabolism , Blood-Brain Barrier/physiopathology , Diabetes Complications/metabolism , Pericytes/metabolism , AIDS Arteritis, Central Nervous System/physiopathology , Actin Cytoskeleton/metabolism , Cell Adhesion Molecules/metabolism , Dementia, Vascular/etiology , Diabetes Complications/physiopathology , Humans , Hyperglycemia/complications , Hyperglycemia/metabolism , Microvessels/metabolism , Primary Cell CultureABSTRACT
The neutral sphingomyelinases (N-SMases) are a group of Mg²âº-dependent enzymes with a pH optimum in the neutral range. N-SMases catalyze the conversion of sphingomyelin to ceramide and have been found particularly enriched in brain tissue. N-SMase activity has been implicated in many physiological and pathological processes affecting the brain and nervous system. In this review, we discuss the proposed functions of N-SMase with a particular emphasis on its role in neurological disorders, such as age-related neurodegeneration, Alzheimer's disease, HIV-associated dementia, atherosclerosis, ischemia-reperfusion injury, and cancer.
Subject(s)
Neurodegenerative Diseases/enzymology , Sphingomyelin Phosphodiesterase/physiology , AIDS Arteritis, Central Nervous System/physiopathology , Aging , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Apoptosis/physiology , Atherosclerosis/complications , Brain Chemistry , Ceramides/metabolism , Encephalitis/complications , Humans , Hydrogen-Ion Concentration , Magnesium/pharmacology , Mice , Mice, Knockout , Neoplasms/physiopathology , Neurodegenerative Diseases/physiopathology , Rats , Reperfusion Injury/etiology , Signal Transduction/physiology , Sphingolipids/metabolism , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Thromboembolism/etiologyABSTRACT
Arteriopathy associated with human immunodeficiency virus infection and clinical acquired immunodeficiency syndrome is well-documented. The pathophysiology of this arteriopathy may vary in different vascular beds. Although arteriopathy of central nervous system (CNS) circulation has been recognized in pediatric patients since the late 1980s, there are no reported cases of CNS arteriopathy in adults. We present the first reported case of adult CNS arteriopathy in a human immunodeficiency virus-positive patient who succumbed to complications secondary to diffuse aneurysmal disease of the Circle of Willis.
