Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease

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)-1 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 (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (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 beta-amyloid (A beta) accumulation. Analysis of APP metabolism suggested that delayed A beta 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 nIGF1R(-/-) Tg2576 mice were protected from premature death in the presence of decreased A beta 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 amodel of AD.-Freude, S., Hettich, M. M., Schumann, C., Stohr, O., Koch, L., Kohler, C., Udelhoven, M., Leeser, U., Muller, M., Kubota, N., Kadowaki, T., Krone, W., Schroder, H., Bruning, J. C., Schubert, M. Neuronal IGF-1 resistance reduces A beta accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J. 23, 3315-3324 ( 2009). www.fasebj.org