TY - JOUR
T1 - HSV-1 promotes Ca2+-mediated APP phosphorylation and Aβ accumulation in rat cortical neurons
AU - Piacentini, Roberto
AU - Civitelli, Livia
AU - Ripoli, Cristian
AU - Marcocci, Maria Elena
AU - De Chiara, Giovanna
AU - Garaci, Enrico
AU - Azzena, Gian Battista
AU - Palamara, Anna Teresa
AU - Grassi, Claudio
PY - 2011
Y1 - 2011
N2 - 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 Ca2+ signals that significantly increased intraneuronal Ca2+ levels. It also enhanced activity- and Ca2+-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.
AB - 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 Ca2+ signals that significantly increased intraneuronal Ca2+ levels. It also enhanced activity- and Ca2+-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.
KW - Amyloid Beta Protein
KW - Herpes Simplex Type-1
KW - Amyloid Beta Protein
KW - Herpes Simplex Type-1
UR - http://hdl.handle.net/10807/13673
M3 - Article
SN - 0197-4580
SP - 2323.e13-2323.e26
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -