Fig. 4

Impaired insulin signalling sub-pathways in AD. Major biochemical reactions related to insulin signalling along with some of the major reactions involved in AD and PD also involve TNFα. In the AD brain, mutated Aβ gets aggregated, accumulated and forms oligomers that activated microglia that secreted TNFα along with other cytokines. Similarly, activated microglia during neuroinflammation may release the same kind of inflammatory cytokines. Both these processes can jointly increase the excess TNFα release concurrently that may inhibit the IRS-1 phosphorylation. PI3k is another factor that may result in phosphorylation of tau and formation of neurofibrillary tangles in AD. Low insulin concentration in the brain reduces the IDE, an enzyme that degrades Aβ, which in turn leads to the formation of tangles and gradual accumulation of Aβ. In AD, soluble Aβ oligomers also block IR that disturbs the normal downstream processing of insulin signalling leading to cell death. Reduced IR signalling also can affect PI3k signalling pathway and results in the upregulation of tangles and Aβ formation. This may lead to the activation of microglia by increasing the level of TNFα and other cytokines, inhibits IR, and generate oxidative stress ultimately leading to cell death