ABSTRACT
Cholesterol, a crucial component of cell membranes, influences various biological processes, including membrane trafficking, signal transduction, and host-pathogen interactions. Disruptions in cholesterol homeostasis have been linked to congenital and acquired conditions, including neurodegenerative disorders such as Alzheimer's disease (AD). Previous research from our group has demonstrated that herpes simplex virus type I (HSV-1) induces an AD-like phenotype in several cell models of infection. This study explores the interplay between cholesterol and HSV-1-induced neurodegeneration. The impact of cholesterol was determined by modulating its levels with methyl-beta-cyclodextrin (MßCD) using the neuroblastoma cell lines SK-N-MC and N2a. We have found that HSV-1 infection triggers the intracellular accumulation of cholesterol in structures resembling endolysosomal/autophagic compartments, a process reversible upon MßCD treatment. Moreover, MßCD exhibits inhibitory effects at various stages of HSV-1 infection, underscoring the importance of cellular cholesterol levels, not only in the viral entry process but also in subsequent post-entry stages. MßCD also alleviated several features of AD-like neurodegeneration induced by viral infection, including lysosomal impairment and intracellular accumulation of amyloid-beta peptide (Aß) and phosphorylated tau. In conclusion, these findings highlight the connection between cholesterol, neurodegeneration, and HSV-1 infection, providing valuable insights into the underlying mechanisms of AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Cholesterol , Herpes Simplex , Herpesvirus 1, Human , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/physiology , Cholesterol/metabolism , Humans , Amyloid beta-Peptides/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/virology , Alzheimer Disease/pathology , Alzheimer Disease/drug therapy , Herpes Simplex/virology , Herpes Simplex/metabolism , Herpes Simplex/drug therapy , Herpes Simplex/pathology , Cell Line, Tumor , Animals , beta-Cyclodextrins/pharmacology , Lysosomes/metabolism , Lysosomes/drug effects , tau Proteins/metabolism , Phenotype , MiceABSTRACT
Growing evidence supports that chronic or latent infection of the central nervous system might be implicated in Alzheimer's disease (AD). Among them, Herpes simplex virus type 1 (HSV-1) has emerged as a major factor in the etiology of the disease. Our group is devoted to the study of the relationship among HSV-1, oxidative stress (OS) and neurodegeneration. We have found that HSV-1 induces the main neuropathological hallmarks of AD, including the accumulation of intracellular amyloid beta (Aß), hyperphosphorylated tau protein and autophagic vesicles, that OS exacerbates these effects, and that matrix metalloproteinase 14 (MMP-14) participates in the alterations induced by OS. In this work, we focused on the role of MMP-14 in the degenerative markers raised by HSV-1 infection. Interestingly, we found that MMP-14 blockage is a potent inhibitor of HSV-1 infection efficiency, that also reduces the degeneration markers, accumulation of Aß and hyperphosphorylated tau, induced by the virus. Our results point to MMP-14 as a potent antiviral target to control HSV-1 infection and its associated neurodegenerative effects.
Subject(s)
Herpes Simplex/metabolism , Herpesvirus 1, Human/physiology , Matrix Metalloproteinase 14/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/virology , Amyloid beta-Peptides/metabolism , Animals , Antiviral Agents/pharmacology , Autophagosomes/metabolism , Biomarkers/metabolism , Cell Line, Tumor , Herpes Simplex/virology , Herpesvirus 1, Human/drug effects , Humans , Matrix Metalloproteinase 14/deficiency , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Neuroblastoma/pathology , Oxidative Stress , Phosphorylation , tau Proteins/metabolismABSTRACT
We report a case of a 39 year-old Asian man in whom profound lower limb paralysis, along with severe hypokalemia and electrocardiographic changes, were the presenting features of Graves' disease (GD)-related thyrotoxicosis. Rapid recognition and management of the disorder were the key factors to avoid fatal hypokalemia-induced cardiac arrhythmias and promptly restore patient's capacity to ambulate.
