Dysregulated APP expression and α-secretase processing of APP is involved in manganese-induced cognitive impairment.

Excessive exposure to manganese (Mn) can cause cognitive impairment, a common feature of Alzheimer's disease (AD), but the mechanisms remain unclear. Amyloid precursor protein (APP) is key to AD pathogenesis, and whether APP and its secretase processing are involved in Mn-induced cognitive impairment remains unknown. In the present study, we established a model of Mn-induced neurotoxicity in vivo (male C57BL/6, 0-100 mg/kg Mn, 90 days, gastric gavage) and in vitro (Neuro-2a (N2a) cells, 0-800 μM Mn for 24 h; APP overexpression and APP shRNA N2a cells, 0 and 800 μM Mn for 24 h). We found impaired cognition of Mn-treated mice. Both in vivo and in vitro results consistently showed that Mn exposure inhibited the expression of APP, α-secretase, soluble APP alpha protein (sAPPα), and synapse proteins as well as the activity of α-secretase. However, Mn exposure showed no effect on the protein levels of β-secretase, Aβ40, and Aβ42 or the activity of β-secretase. Collectively, these findings demonstrate key roles of APP and its α-secretase processing in the regulation of Mn-induced cognitive impairment, which may act as a target for ameliorating Mn-induced neurotoxicity.