(A) In healthy aging, IRs are present at synapses, and proper insulin signaling favors synapse function and leads to memory formation. (B) In early AD, accumulation of AβOs stimulates TNF-α signaling, which activates the JNK pathway (11, 54) and, possibly, PKR and IKK pathways. Activation of these stress-sensitive kinases, which can also be triggered by ER stress in peripheral tissues (69), results in IRS-1pSer, decreasing downstream insulin signaling (11, 31, 54). This contributes to initial cognitive impairment in early AD. (C) At later AD stages, increased accumulation of AβOs and their binding to synapses lead to removal of IRs from the neuronal plasma membrane (14, 15, 47). Additionally, TNF-α/JNK activation ultimately blocks insulin actions (11), contributing to severe impairment in cognition and memory. (D) Stimulation of insulin and GLP-1Rs blocks early AβO-induced defects in insulin signaling. Insulin protects neurons by preventing AβO binding to neurons (15). In addition, activation of GLP-1Rs by exendin-4 or liraglutide and of IRs by insulin prevents JNK activation, allowing physiological tyrosine phosphorylation of IRS-1 and stimulating downstream insulin signaling. (E) At later AD stages, activation of GLP-1Rs prevents inhibitory IRS-1pSer, stimulating insulin-related downstream signaling pathways and ameliorating cognitive and memory impairment. Red arrows indicate inhibitory pathways and green arrows indicate stimulatory pathways of insulin signaling.