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, 2011?and?de la Monte, 2009), which is associated with decreased BBB function induced by continuous peripheral hyperinsulinemia (Bosco et al., 2011?and?Li and Holscher, 2007). However, neurons in brain also express and secrete the insulin (Kuwabara et al., 2011), and in AD brain, insulin mRNA expression was 4-fold lower in the hippocampus and 2-fold lower in the hypothalamus compared to control brains (Steen et al., 2005). Thus, both mechanisms of transportation disruption and local secretion dysfunction can induce the declined insulin level in AD brain. Beyond the above-mentioned mechanisms, impaired binding between insulin, IGF-1 and their receptors also was observed in AD, which is associated with changes in membrane cholesterol levels which affected the membrane dynamics upon aging and/or APOE4 Ceritinib genotype (de la Monte, 2009?and?Li and Holscher, 2007). Chua et al. (2012) has demonstrated that impaired insulin signaling precedes A�� accumulation, which implies the importance of reduced insulin signaling among pathogenic factors of Alzheimer's neurodegeneration. Insulin/IGF-1 signaling defects Vorinostat chemical structure predominantly involve in phosphatidylinositide 3-kinases (PI3K)/Akt pathway through producing harmful cascades in glucose metabolism (Liu et al., 2011). It was recently proposed that decreased expression and function of PI3K/Akt-mediated GLUTs in AD brain could lead to brain glucose hypometabolism and the subsequent decline in mitochondrial ATP production (Bosco heptaminol et al., 2011). By comparing the function of brain insulin-PI3K-Akt signaling pathway in the frontal cortices of AD, T2DM, T2DM with AD, and control subjects, Liu et al. (2011) found that the de?ciency of insulin-PI3K-Akt signaling was more significant in subjects with both T2DM and AD. Furthermore, their studies also showed that the levels and the activation of the insulin-PI3K-Akt signaling components correlated negatively with the level of tau phosphorylation and positively with tau O-GlcNAcylation, suggesting that impaired insulin-PI3K-Akt signaling might contribute to neurodegeneration in AD through decreased O-GlcNAcylation and consequent tau hyperphosphorylation. Recently, Bomfim et al. (2012) reported that A�� oligomers could activate the tumor necrosis factor ��/c-Jun N-terminal kinase pathway, induce IR substrate-1 (IRS-1) phosphorylation at multiple serine residues, and inhibit physiological phosphorylated IRS-1 (at Tyr896) in cultured hippocampal neurons. Moreover, the impairment of IRS-1 signaling was also observed in APP/PS1 transgenic mice as well as in cynomolgus monkeys intraventricularly injected with A�� oligomers (Bomfim et al., 2012). Similar pathophysiological alterations were also found in human AD brains by Talbot et al. (2012). These results showed that AD patients with T2DM may be closely associated with IRS-1 dysregulation and IGF-1 resistance.