title: Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease.
abstract: 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, β-amyloid (Aβ)(1-42) and Aβ(1-40). Recently, we and others have shown that central IGF-1 resistance reduces Aβ accumulation as well as Aβ 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 Aβ burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-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 α- as well as β-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 Aβ accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription.
authors: Center for Endocrinology, Diabetes and Preventive Medicine, Center for Molecular Medicine Cologne, University of Cologne, Kerpener Str 62, Cologne, Germany.
authors: Oliver
authors: O
authors: Stöhr
authors: Katharina
authors: K
authors: Schilbach
authors: Lorna
authors: L
authors: Moll
authors: Moritz M
authors: MM
authors: Hettich
authors: Susanna
authors: S
authors: Freude
authors: F Thomas
authors: FT
authors: Wunderlich
authors: Marianne
authors: M
authors: Ernst
authors: Johanna
authors: J
authors: Zemva
authors: Jens C
authors: JC
authors: Brüning
authors: Wilhelm
authors: W
authors: Krone
authors: Michael
authors: M
authors: Udelhoven
authors: Markus
authors: M
authors: Schubert
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D055504:Insulin Receptor Substrate Proteins; D011972:Receptor, Insulin