| First Author | Stöhr O | Year | 2013 |
| Journal | Age (Dordr) | Volume | 35 |
| Issue | 1 | Pages | 83-101 |
| PubMed ID | 22057897 | Mgi Jnum | J:301891 |
| Mgi Id | MGI:6507229 | Doi | 10.1007/s11357-011-9333-2 |
| Citation | Stohr O, et al. (2013) Insulin receptor signaling mediates APP processing and beta-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease. Age (Dordr) 35(1):83-101 |
| abstractText | In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, beta-amyloid (Abeta)(1-42) and Abeta(1-40). Recently, we and others have shown that central IGF-1 resistance reduces Abeta accumulation as well as Abeta toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR(-/-)Tg2576) mice leads to markedly decreased Abeta burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased alpha-/beta-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases alpha- as well as beta-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Abeta accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of beta-amyloid accumulation and FoxO1-mediated transcription. |
