Impaired neuronal insulin signaling precedes Aβ42 Accumulation in female AβPPsw/PS1ΔE9 Mice

Li Min Chua, Mei Li Lim, Pey Rou Chong, Ze Ping Hu, Nam Sang Cheung, Boon Seng Wong

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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-β (Aβ) biogenesis is unclear. In this study using female AβPPsw/PS1ΔE9 mice, we found that the level of Aβ40 was fairly constant in 6-to 15-month-old brains, whereas Aβ42 was only significantly increased in the 15-month-old brain. In contrast, increased levels of IRβ, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AβPPsw/PS1ΔE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aβ42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AβPPsw/PS1ΔE9 mouse brain. Furthermore, the expression profile of IRβ, IRS-2, and p85/PI3K in AβPPsw/PS1ΔE9 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 AβPPsw/ PS1ΔE9 mice.

Original languageEnglish (US)
Pages (from-to)783-791
Number of pages9
JournalJournal of Alzheimer's Disease
Volume29
Issue number4
DOIs
StatePublished - 2012

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Keywords

  • Alzheimer's disease
  • amyloid
  • glucose transporter
  • insulin signaling
  • neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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