Neuronal insulin resistance reduces Alzheimer-like pathology in Tg2576 mice independent of Foxo1 mediated transcription

Dysregulation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway are associated with Alzheimer's disease (AD). To elucidate the role of IR signaling and the downstream transcription factor Foxo1 in the pathogenesis of AD we used conditional mutagenesis in mice. In order to analyze the role of IR signaling and the Foxo1 transcription factors in the pathogenesis of AD we crossed neuron-specific IR deficient mice (nIR-/-) and mice expressing either a dominant negative (Foxo1DN) or a constitutively active Foxo1 (Foxo1ADA) with Tg2576 mice overexpressing the Swedish mutant of the amyloid precursor protein (APP). The offspring of these mice was analyzed in respect to survival, amyloid accumulation, and APP processing. Interestingly, Tg2576 mice with neuronal deficiency for the IR gene accumulated significantly less beta-amyloid compared to Tg2576 mice. Analyzing APP c-terminal fragments (CTF) revealed decreased alpha-/beta-CTFs in brains of nIR-/-Tg2576 mice compared to 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. In contrast to previous reports of IGF-1R deficient Tg2576 mice IR deletion did not rescue premature mortality in Tg2576 mice. Furthermore, we have demonstrated that Foxo1 is the most abundant Foxo1 expressed in the hippocampus. In the analysis of mice expressing neuron-specific either a dominant negative or constitutively active form of Foxo1 in a Tg2576 background neither Foxo1ADATg2576 nor Foxo1DNTg2576 mice revealed any alteration of beta-amyloid burden, APP processing or survival. These data suggest that the effects mediated by IR or IGF-1R are independent of Foxo1. Neuron-specific IR deficiency reduces ß-amyloid accumulation at least partially via decreased APP processing without influencing premature mortality in Tg2576 mice independently of Foxo1 mediated transcription.