Several data indicate that neuronal infection with herpes simplex virus
type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's
disease (AD) phenotype. They include accumulation of amyloid-β (Aβ),
which originates from the cleavage of amyloid precursor protein (APP),
and hyperphosphorylation of tau protein, which leads to neurofibrillary
tangle deposition. HSV-1 infection triggers APP processing and drives
the production of several fragments including APP intracellular domain
(AICD) that exerts transactivating properties. Herein, we analyzed the
production and intracellular localization of AICD following HSV-1
infection in neurons. We also checked whether AICD induced the
transcription of two target genes, neprilysin (nep) and glycogen
synthase kinase 3β (gsk3β), whose products play a role in Aβ clearance
and tau phosphorylation, respectively. Our data indicate that HSV-1 led
to the accumulation and nuclear translocation of AICD in neurons.
Moreover, results from chromatin immunoprecipitation assay showed that
AICD binds the promoter region of both nep and gsk3β. Time course
analysis of NEP and GSK3β expression at both mRNA and protein levels
demonstrated that they are differently modulated during infection. NEP
expression and enzymatic activity were initially stimulated but, with
the progression of infection, they were down-regulated. In contrast,
GSK3β expression remained nearly unchanged, but the analysis of its
phosphorylation suggests that it was inactivated only at later stages of
HSV-1 infection. Thus, our data demonstrate that HSV-1 infection
induces early upstream events in the cell that may eventually lead to Aβ
deposition and tau hyperphosphorylation and further suggest HSV-1 as a
possible risk factor for AD.
type 1 (HSV-1) causes biochemical alterations reminiscent of Alzheimer's
disease (AD) phenotype. They include accumulation of amyloid-β (Aβ),
which originates from the cleavage of amyloid precursor protein (APP),
and hyperphosphorylation of tau protein, which leads to neurofibrillary
tangle deposition. HSV-1 infection triggers APP processing and drives
the production of several fragments including APP intracellular domain
(AICD) that exerts transactivating properties. Herein, we analyzed the
production and intracellular localization of AICD following HSV-1
infection in neurons. We also checked whether AICD induced the
transcription of two target genes, neprilysin (nep) and glycogen
synthase kinase 3β (gsk3β), whose products play a role in Aβ clearance
and tau phosphorylation, respectively. Our data indicate that HSV-1 led
to the accumulation and nuclear translocation of AICD in neurons.
Moreover, results from chromatin immunoprecipitation assay showed that
AICD binds the promoter region of both nep and gsk3β. Time course
analysis of NEP and GSK3β expression at both mRNA and protein levels
demonstrated that they are differently modulated during infection. NEP
expression and enzymatic activity were initially stimulated but, with
the progression of infection, they were down-regulated. In contrast,
GSK3β expression remained nearly unchanged, but the analysis of its
phosphorylation suggests that it was inactivated only at later stages of
HSV-1 infection. Thus, our data demonstrate that HSV-1 infection
induces early upstream events in the cell that may eventually lead to Aβ
deposition and tau hyperphosphorylation and further suggest HSV-1 as a
possible risk factor for AD.
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