The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress

The causal agent(s) and molecular mechanisms of Alzheimer's disease (AD) remain unclear. Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) infection is involved in the AD pathogenesis. Oxidative stress (OS) may also be crucial in the AD development. Our group previously reported that both HSV-1 and OS trigger the appearance of AD-type neurodegeneration markers. The main aim of the present study was to identify the mechanisms involved in this triggering. Expression studies revealed the involvement of a set of OS-regulated genes in HSV-1-infected cells and in cells harboring the Swedish mutation of the amyloid beta precursor protein gene. Functional annotation of these genes revealed the lysosome system to be impaired, suggesting that the interaction of OS with both HSV-1 and amyloid beta precursor protein mutations affects lysosomal function. Functional studies revealed HSV-1 infection and OS to increase the lysosome load, reduce the activity of lysosomal hydrolases, affect cathepsin maturation, and inhibit the endocytosis-mediated degradation of the epidermal growth factor receptor. These findings suggest alterations in the lysosome system to be involved in different forms of AD.