IRS1 and Alzheimer disease: Aβ oligomers (AβOs), synaptotoxins that accumulate in AD brains, impaired neuronal insulin signaling via activation of TNFα and stress-related kinases, including the IκB kinase (IKK), c-Jun N-terminal kinase (JNK), and double-stranded RNA-dependent protein kinase (PKR), which induced the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and caused serine phosphorylation of insulin receptor substrate (IRS)-1 (IRS-1pSer), while inhibiting the physiological tyrosine phosphorylation of IRS-1 (IRS-1pTyr).