APP and Alzheimer disease: Whereas at the first, asymptomatic, AD stage, the AβPP-derived iAβ-initiated cascade is relatively benign and involves the activation of eIF2α kinases and elicitation of the ISR, at the second AD stage iAβ produced independently of AβPP drives a much more perilous cascade that involves the formation, presumably through a chain of events, including the iAβ-mediated inhibition of the ubiquitin–proteasome system [134,135,136,137], of tau tangles, and ultimately results in neuronal loss.