Reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease

Herpes simplex virus type 1 (HSV-1) has been proposed as an environmental risk factor for sporadic Alzheimer's disease, although this issue is still in dispute. The involvement of HSV-1 in the pathogenesis of familial Alzheimer's disease, the uncommon type of Alzheimer's disease, has not been addressed yet. We investigated formalin-fixed, paraffin-embedded, postmortem brain tissue sections of three patients with familial Alzheimer's disease for the presence of HSV-1 DNA. The nested polymerase chain reaction (PCR) detected the HSV-1 glycoprotein D gene in the brain of all three patients with familial Alzheimer's disease preferentially in the frontal and temporal cortices, whereas only one case out of six age-matched, non-Alzheimer's disease individuals could disclose the presence of HSV-1 gene. The PCR detected HSV-1 DNA in the frontal cortex of the two patients with sporadic Alzheimer's disease. The presence of HSV-1 was associated with beta-amyloid deposition in the cerebral cortex. To clarify the localization of HSV-1 in the brain tissue of patients with familial Alzheimer's disease, the in situ hybridization of the tyramide signal amplification system was used. It detected the HSV-1-specific signals predominantly in the cytoplasm of cortical neurons in a dot-like staining fashion. In addition, high-sensitivity immunohistochemistry revealed the existence of HSV-1 antigens in the cytoplasm of cortical neurons. This report provides the first evidence of reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease, associated with beta-amyloid deposition, and suggests the possible involvement of HSV-1 together with genetic factors in the pathogenesis of familial Alzheimer's disease.