Microbial infection as a type of environmental risk factors is considered to be associated with long-term increased risk of dementia, including Alzheimer's disease (AD). AD is characterized by two neuropathologically molecular hallmarks of hyperphosphorylated tau and amyloid-beta (A beta), the latter generated by several biochemically reactive enzymes, including gamma-secretase. However, how infectious risk factors contribute to pathological development of the AD core molecules remains to be addressed. In this work, we utilized a modified herpes simplex virus type 1 (mHSV-1) and found that its hippocampal infection locally promotes A beta pathology in 5 x FAD mice, the commonly used amyloid model. Mechanistically, we identified HSV-1 membrane glycoprotein US7 (Envelope gI) that interacts with and modulates gamma-secretase and consequently facilitates A beta production. Furthermore, we presented evidence that adenovirus-associated virus-mediated locally hippocampal overexpression of the US7 aggravates A beta pathology in 5 x FAD mice. Collectively, these findings identify a herpesviral factor regulating gamma-secretase in the development and progression of AD and represent a causal molecular link between infectious pathogens and neurodegeneration.