Accumulating data suggest a potential link between HSV-1 infection and Alzheimer's disease (AD). Our previous in vitro studies showed that HSV-1infection in neurons triggers i) the amyloidogenic processing of amyloid precursor protein (APP) causing intra-and extraneuronal accumulation of beta amyloid peptides (A?s), and of C-Terminal APP-fragments (CTFs) (Piacentini et al, 2011; De Chiara et al, 2010); ii) CTFs nuclear translocation which modulates the transcription of GSK-3? and Neprilysin (Civitelli et al, 2015); iii) synaptic dysfunction via GSK-3-dependent intraneuronal accumulation of A?s (Piacentini et al, 2015); accumulation of DNA lesions (De Chiara et al, 2016). Herein we performed in vivo studies to investigate whether recurrent HSV-1 infections may result in an AD-like phenotype during ageing. To this aim, 6-8 week-old female BALB/c mice were infected by labial HSV-1 inoculation, mimicking common HSV-1 infection in humans, and subjected to multiple thermal stress (TSs) every 6 weeks over the next 10 months to induce repeated virus reactivations, spreading and active replication into the brain. These events were checked by detection of viral TK gene and ICP4 mRNA/protein expression in brain tissues. Immunohistochemistry and western blot analysis on mouse cerebral tissues revealed the occurrence of APP amyloidogenic processing in cortex and hippocampus from HSV-1 infected mice (HSV1-M) with consequent intraneuronal A? accumulation and extraneuronal amyloid plaque deposition, that increased with TS number and mouse ageing. Moreover, altered tau phosphorylation, aggregation and cleavage, together with signs of neuroinflammation were significantly increased in the brain of HSV1-M undergone several TSs as compared to matched control mice (CONTROL-M). Behavioral studies -performed 1 week before and after TSs- showed that each virus reactivation results in significant cognitive deficits in mice, especially when assessed by the Novel object recognition (NOR) test (p<0.05 after the 1st and -3rd TSs; p<0.001 after the 6th TS vs CONTROL-M). On the contrary, no significant difference was found when NOR performance was assessed before the 3rd TS, suggesting that damages caused by few virus reactivations may be promptly recovered during latency. Conversely a significant impairment in NOR performance was observed before the 6th TS (p<0.01), suggesting a virus-related progressive and irreversible accumulation of damages, likely mediated by A?s and phospho-tau. Altogether these data strongly indicate recurrent HSV-1 infections as a potential risk factor for AD.
Recurrent Herpes Simplex type-1 (HSV-1) infections trigger progressive Alzheimer's disease-related neuropathology in mice
2017
Abstract
Accumulating data suggest a potential link between HSV-1 infection and Alzheimer's disease (AD). Our previous in vitro studies showed that HSV-1infection in neurons triggers i) the amyloidogenic processing of amyloid precursor protein (APP) causing intra-and extraneuronal accumulation of beta amyloid peptides (A?s), and of C-Terminal APP-fragments (CTFs) (Piacentini et al, 2011; De Chiara et al, 2010); ii) CTFs nuclear translocation which modulates the transcription of GSK-3? and Neprilysin (Civitelli et al, 2015); iii) synaptic dysfunction via GSK-3-dependent intraneuronal accumulation of A?s (Piacentini et al, 2015); accumulation of DNA lesions (De Chiara et al, 2016). Herein we performed in vivo studies to investigate whether recurrent HSV-1 infections may result in an AD-like phenotype during ageing. To this aim, 6-8 week-old female BALB/c mice were infected by labial HSV-1 inoculation, mimicking common HSV-1 infection in humans, and subjected to multiple thermal stress (TSs) every 6 weeks over the next 10 months to induce repeated virus reactivations, spreading and active replication into the brain. These events were checked by detection of viral TK gene and ICP4 mRNA/protein expression in brain tissues. Immunohistochemistry and western blot analysis on mouse cerebral tissues revealed the occurrence of APP amyloidogenic processing in cortex and hippocampus from HSV-1 infected mice (HSV1-M) with consequent intraneuronal A? accumulation and extraneuronal amyloid plaque deposition, that increased with TS number and mouse ageing. Moreover, altered tau phosphorylation, aggregation and cleavage, together with signs of neuroinflammation were significantly increased in the brain of HSV1-M undergone several TSs as compared to matched control mice (CONTROL-M). Behavioral studies -performed 1 week before and after TSs- showed that each virus reactivation results in significant cognitive deficits in mice, especially when assessed by the Novel object recognition (NOR) test (p<0.05 after the 1st and -3rd TSs; p<0.001 after the 6th TS vs CONTROL-M). On the contrary, no significant difference was found when NOR performance was assessed before the 3rd TS, suggesting that damages caused by few virus reactivations may be promptly recovered during latency. Conversely a significant impairment in NOR performance was observed before the 6th TS (p<0.01), suggesting a virus-related progressive and irreversible accumulation of damages, likely mediated by A?s and phospho-tau. Altogether these data strongly indicate recurrent HSV-1 infections as a potential risk factor for AD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
