부산대학교 도서관

Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-I receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APPsw, Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-IR (nIGF-1R-/-), or neuronal insulin receptor (nIR-/-), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays β-amyloid (Aβ) accumulation. Analysis of APP metabolism suggested that delayed Aβ accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R-/-Tg2576 mice were protected from premature death in the presence of decreased Aβ accumulation specifically in the hippocampus formation. However, neuronal IR-/- deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD. [ABSTRACT FROM AUTHOR]