APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells

• Published in: PloS one 2010-11, Vol.5 (11), p.e13989
• Main Authors: De Chiara, Giovanna, Marcocci, Maria Elena, Civitelli, Livia, Argnani, Rafaela, Piacentini, Roberto, Ripoli, Cristian, Manservigi, Roberto, Grassi, Claudio, Garaci, Enrico, Palamara, Anna Teresa
• Format: Article
• Language: English
• Subjects: Accumulation; Activation; Advertising executives; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloidogenesis; Animals; Apoptosis; Blotting, Western; Brain; Caspase; Caspase-3; Cell culture; Cell Line, Tumor; Cells, Cultured; Central nervous system; Cytotoxicity; Encephalitis; Epidemiology; Formic acid; Fragmentation; Fragments; Gene expression; Genomes; Health aspects; HeLa Cells; Herpes simplex; Herpes simplex virus; Herpes simplex virus 1; Herpes viruses; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - physiology; Host-Pathogen Interactions; Humans; Infection; Infections; Infectious diseases; Infectious Diseases/Infectious Diseases of the Nervous System; Infectious Diseases/Viral Infections; Lipid peroxidation; Lysates; Medical research; Microscopy, Confocal; Mutation; Nervous system; Nervous system diseases; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma - virology; Neuroblastoma cells; Neurodegenerative diseases; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - virology; Neuroscience; Neurotoxicity; Nitric oxide; Oxidative stress; Pathogenesis; Pathology/Neuropathology; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides; Physiology; Protein Multimerization; Proteins; Public health; Rats; Reverse Transcriptase Polymerase Chain Reaction; Risk analysis; Risk factors; Secretase; Trigeminal ganglion; Viral infections; Virions; Virology; Viruses; β-Amyloid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013989

Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During these episodes, newly produced virions may also reach the central nervous system (CNS), causing productive but generally asymptomatic infections. Epidemiological and experimental findings suggest that HSV-1 might contribute to the pathogenesis of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is related to an overproduction of amyloid beta (Aβ) and other neurotoxic peptides, which occurs during amyloidogenic endoproteolytic processing of the transmembrane amyloid precursor protein (APP). The aim of our study was to identify the effects of productive HSV-1 infection on APP processing in neuronal cells. We found that infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is followed by multiple cleavages of APP, which result in the intra- and/or extra-cellular accumulation of various neurotoxic species. These include: i) APP fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions of Aβ; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal APP-Fs; and iv) Aβ(1-40) and Aβ(1-42). Western blot analysis of infected-cell lysates treated with formic acid suggests that APP-F35 may be an Aβ oligomer. The multiple cleavages of APP that occur in infected cells are produced in part by known components of the amyloidogenic APP processing pathway, i.e., host-cell β-secretase, γ-secretase, and caspase-3-like enzymes. These findings demonstrate that HSV-1 infection of neuronal cells can generate multiple APP fragments with well-documented neurotoxic potentials. It is tempting to speculate that intra- and extracellular accumulation of these species in the CNS resulting from repeated HSV-1 reactivation could, in the presence of other risk factors, play a co-factorial role in the development of AD.