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

Abstract

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 (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta 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 Abeta 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.

FoxO6 regulates memory consolidation and synaptic function

“…Activating the insulin/IGF pathway-which is known to inhibit FoxO factors-is important for memory retention and synaptogenesis (O'Kusky et al 2000;Aleman and Torres-Aleman 2009;Chen et al 2011). On the other hand, reducing the insulin/IGF pathwaywhich is known to activate FoxO factors-is important for extending longevity and preventing symptoms of Alzheimer's disease (Cohen et al 2009;Freude et al 2009;Killick et al 2009). It is possible that lowering the levels of insulin/IGF (leading to high FoxO activity) is beneficial for overall life span and some aspects of cognition, such as memory consolidation.…”

“…At the organismal level, the deletion of FoxO1 or FoxO3 results in reduced anxiety-and depression-like behaviors, respectively (Polter et al 2009). Interestingly, the insulin/ IGF pathway, which regulates FoxO transcription factors, has been found to impact learning and memory in physiological or pathological conditions such as Alzheimer's disease (Cohen et al 2009;Freude et al 2009;Killick et al 2009;Chen et al 2011). However, the importance and mode of action of the hippocampal-enriched FoxO6 in cognitive behavior are not known.…”

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

“…Recent data suggest that brain-specific IGF-1 resistance increases longevity (Freude et al 2009;Kappeler et al 2008;Taguchi et al 2007). Furthermore, decreased IGF-1 signaling reduces Aβ toxicity in worms and mice (Cohen et al 2006(Cohen et al , 2009.…”

“…Tg2576 mice develop an age-dependent memory impairment, Aβ accumulation and form extracellular Aβ plaques beginning at the age of 6-8 months (Stein and Johnson 2002). Furthermore, these mice display an increased mortality (Freude et al 2009). To achieve neuron-specific deletion, we crossed mice carrying a floxed exon 4 of the IR gene with mice expressing the Cre recombinase under control of the Syn-Cre.…”

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…Studies using analogues for the gut hormone glucagon-like peptide-1 (GLP-1) such as liraglutide, which facilitate insulin release, have shown that even short-term treatment can improve learning and memory, in addition to improving glucose homeostasis in mice with diet-induced obesity [7]. Moreover, an increase of GLP-1 signalling in the brain has also been suggested as a promising strategy to ameliorate the degenerative processes observed in Alzheimer's disease [8], while studies crossing APP mice to mouse models with alterations in brain insulin-signalling have revealed an important role for insulin signalling and glucose homeostasis in cognitive behaviour in these mice [9][10][11].…”