Impaired Neuronal Insulin Signaling Precedes Aβ42 Accumulation in Female AβPPsw/PS1ΔE9 Mice

Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer's disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-beta (A beta) biogenesis is unclear. In this study using female A beta PPsw/PS1 Delta E9 mice, we found that the level of A beta(40) was fairly constant in 6- to 15-month-old brains, whereas A beta(42) was only significantly increased in the 15-month-old brain. In contrast, increased levels of IR beta, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of A beta PPsw/PS1 Delta E9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of A beta(42) level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old A beta PPsw/PS1 Delta E9 mouse brain. Furthermore, the expression profile of IR beta, IRS-2, and p85/PI3K in A beta PPsw/PS1 Delta E9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in A beta PPsw/PS1 Delta E9 mice.