title: HSV-1 promotes Ca2+ -mediated APP phosphorylation and Aβ accumulation in rat cortical neurons.
abstract: Epidemiological and experimental findings suggest that chronic infection with Herpes simplex virus type 1 (HSV-1) may be a risk factor for Alzheimer's disease (AD), but the molecular mechanisms underlying this association have not been fully identified. We investigated the effects of HSV-1 on excitability and intracellular calcium signaling in rat cortical neurons and the impact of these effects on amyloid precursor protein (APP) processing and the production of amyloid-β peptide (Aβ). Membrane depolarization triggering firing rate increases was observed shortly after neurons were challenged with HSV-1 and was still evident 12 hours postinfection. These effects depended on persistent sodium current activation and potassium current inhibition. The virally induced hyperexcitability triggered intracellular Ca(2+) signals that significantly increased intraneuronal Ca(2+) levels. It also enhanced activity- and Ca(2+)-dependent APP phosphorylation and intracellular accumulation of Aβ42. These findings indicate that HSV-1 causes functional changes in cortical neurons that promote APP processing and Aβ production, and they are compatible with the co-factorial role for HSV-1 in the pathogenesis of AD suggested by previous findings.
authors.affiliation: Institute of Human Physiology, Catholic University Medical School, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Piacentini
authors.forename: Livia
authors.initials: L
authors.lastname: Civitelli
authors.forename: Cristian
authors.initials: C
authors.lastname: Ripoli
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Marcocci
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Chiara
authors.forename: Enrico
authors.initials: E
authors.lastname: Garaci
authors.forename: Gian Battista
authors.initials: GB
authors.lastname: Azzena
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D008564:Membrane Potentials / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D015854:Up-Regulation / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002118:Calcium