Journal
NEUROBIOLOGY OF AGING
Volume 32, Issue 12, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2010.06.009
Keywords
Intracellular Ca2+ signals; Ca(v)1 channels; Herpes simplex virus type 1; Amyloid-beta peptide; Persistent Na+ currents; Amyloid precursor protein; APP phosphorylation; Alzheimer's disease
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Funding
- Italian Ministry of Education University and Research
- Italian Ministry of Health
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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-beta peptide (A beta). 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 A beta 42. These findings indicate that HSV-1 causes functional changes in cortical neurons that promote APP processing and A beta production, and they are compatible with the co-factorial role for HSV-1 in the pathogenesis of AD suggested by previous findings. (C) 2011 Elsevier Inc. All rights reserved.
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