Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation.
Increasing evidence suggests that recurrent Herpes Simplex Virus type 1 (HSV-1) infection spreading to the CNS is a risk factor for Alzheimer's Disease (AD) but the underlying mechanisms have not been fully elucidated yet. Here we demonstrate that in cultured mouse cortical neurons HSV-1 induced Ca(2+)-dependent activation of glycogen synthase kinase (GSK)-3. This event was critical for the HSV-1-dependent phosphorylation of amyloid precursor protein (APP) at Thr668 and the following intraneuronal accumulation of amyloid-β protein (Aβ). HSV-1-infected neurons also exhibited: i) significantly reduced expression of the presynaptic proteins synapsin-1 and synaptophysin; ii) depressed synaptic transmission. These effects depended on GSK-3 activation and intraneuronal accumulation of Aβ. In fact, either the selective GSK-3 inhibitor, SB216763, or a specific antibody recognizing Aβ (4G8) significantly counteracted the effects induced by HSV-1 at the synaptic level. Moreover, in neurons derived from APP KO mice and infected with HSV-1 Aβ accumulation was not found and synaptic protein expression was only slightly reduced when compared to wild-type infected neurons. These data further support our contention that HSV-1 infections spreading to the CNS may contribute to AD phenotype.
Institute of Human Physiology, Medical School, Università Cattolica, 00168 Rome, Italy.
Roberto
R
Piacentini
Institute of Human Physiology, Medical School, Università Cattolica, 00168 Rome, Italy.
Domenica Donatella
DD
Li Puma
Institute of Human Physiology, Medical School, Università Cattolica, 00168 Rome, Italy.
Cristian
C
Ripoli
Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.
Maria Elena
ME
Marcocci
Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy.
Giovanna
G
De Chiara
San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00163 Rome, Italy.
Enrico
E
Garaci
Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.|San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00163 Rome, Italy.
Anna Teresa
AT
Palamara
Institute of Human Physiology, Medical School, Università Cattolica, 00168 Rome, Italy.|San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00163 Rome, Italy.
Claudio
C
Grassi
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012307:Risk Factors; D016704:Synapsins / Q000096:biosynthesis* / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D016708:Synaptophysin / Q000096:biosynthesis* / Q000235:genetics
D016229:Amyloid beta-Peptides; D016704:Synapsins; D016708:Synaptophysin; D038362:Glycogen Synthase Kinase 3