Figure 2.

Simplified summary of proposed neuroprotective mechanisms of amyloid precursor protein (APP) and APPsα in response to acute stress. Expression of APP is upregulated in response to acute metabolic insult. As depicted in Figure 1, NMDAR and LTCC are pathologically activated, promoting excitotoxic cellular damage. Cleavage of APP is activity-dependent and α-secretases are stimulated by NMDAR, generating the neuroprotective APPsα fragment. APPsα acts inhibitory on NMDAR and LTCC. This negative feedback mechanism may breach the vicious cycle of excitotoxicity and constitute an important protective mechanism in response to acute insults. Several further trophic, regulatory and anti-apoptotic functions of APP and APPsα are listed. They may contribute to acute neuroprotective effect on multiple levels. Since exact mechanisms of interaction are oftentimes not known, this ambiguity is represented by dashed arrows. The triple period below indicates that the list makes no claims of being complete since many more mechanisms are being discussed.