Our results show, surprisingly, that Mn alone did not affect APP and BACE1 expression and Aβ generation; in APPsw-N2a cells, in contrast, when the APPsw-N2a cells were cocultured with microglia or cultured in a microglia-conditioned medium, Mn treatment increased the expression level of APP, BACE1, amyloidogenic C99 fragment, and Aβ; we also found that Mn treatment increased microglia-released inflammatory cytokines IL-1β and TNF-α in microglia culture and an increase in activated microglia in 3×Tg-AD mouse brains. Here, BACE1 is linked to Alzheimer disease.