The role of impaired brain insulin signaling in sporadic Alzheimer’s disease (sAD) pathology. Disturbance of brain insulin signaling has been suggested to be a key causative event underlying sAD etiopathogenesis, being linked to the presence of the two major pathological features of this neurodegenerative disorder, senile plaques and neurofibrillary tangles (NFTs). Indeed, impaired insulin/insulin receptor (IR) signaling leads to decreased insulin-mediated activation of phosphoinositide 3-kinase (PI3-K)/Akt signaling activity, resulting in overactivation of glycogen synthase kinase-3β (GSK-3β). Consequently, GSK-3β overactivation directly promotes tau hyperphosphorylation and formation of NFTs, as well as amyloid-β (Aβ) accumulation and senile plaques formation. Additionally, disruption of insulin signaling leads to a decreased glucose transporter-1 (GLUT-1) and -3 (GLUT-3) expression, culminating in impaired cerebral glucose uptake/metabolism. Moreover, it was recently proposed that decreased neuronal glucose metabolism results in decreased level of UDP-GlcNAc via the hexosamine biosynthetic pathway (HBP) and, consequently, decreased tau O-GlcNAcylation, thus potentiating tau hyperphosphorylation. Overall, impaired brain insulin signaling seems to be a plausible trigger of neuronal dysfunction and cognitive decline in sAD.

Schematic illustration of insulin resistance-mediated amyloid-β (Aβ) peptide deposition via a mechanism involving insulin-degrading enzyme (IDE). Aβ is mainly degraded by IDE, in the extracellular space. Under hyperinsulinemic conditions associated with insulin resistance, IDE might be competitively inhibited by insulin, resulting in an increased Aβ deposition and senile plaques formation