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Sci Rep. 2015 Oct 21;5:15444. doi: 10.1038/srep15444.

Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation.

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Institute of Human Physiology, Medical School, Università Cattolica, 00168 Rome, Italy.
Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.
Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy.
San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care, 00163 Rome, Italy.


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.

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