IRS1 and Insulin resistance: On the other hand, APP-Aβ oligomers are toxic and can induce or exacerbate neuronal insulin resistance by the abnormal activation of the TNF-α/JNK (tumor necrosis factor alpha/c-Jun N-terminal kinase) pathway, leading to the serine phosphorylation of IRS-1 [92,154,172,173], and by the induction of mitochondrial oxidative stress [174,175,176].