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-? protein (A?). 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 A?. In fact, either the selective GSK-3 inhibitor, SB216763, or a specific antibody recognizing A? (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 A? 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.
Herpes Simplex Virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-? protein accumulation
De Chiara G;
2015
Abstract
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-? protein (A?). 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 A?. In fact, either the selective GSK-3 inhibitor, SB216763, or a specific antibody recognizing A? (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 A? 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
