IGF-1-induced Processing of the Amyloid Precursor Protein Family Is Mediated by Different Signaling Pathways

Department of Neurochemistry, Stockholm University, SE-10691 Stockholm, Sweden.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(14):10203-9. DOI: 10.1074/jbc.M611183200
Source: PubMed


The mammalian amyloid precursor protein (APP) protein family consists of the APP and the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). The neurotoxic amyloid beta-peptide (Abeta) originates from APP, which is the only member of this protein family implicated in Alzheimer disease. However, the three homologous proteins have been proposed to be processed in similar ways and to have essential and overlapping functions. Therefore, it is also important to take into account the effects on the processing and function of the APP-like proteins in the development of therapeutic drugs aimed at decreasing the production of Abeta. Insulin and insulin-like growth factor-1 (IGF-1) have been shown to regulate APP processing and the levels of Abeta in the brain. In the present study, we show that IGF-1 increases alpha-secretase processing of endogenous APP and also increases ectodomain shedding of APLP1 and APLP2 in human SH-SY5Y neuroblastoma cells. We also investigated the role of different IGF-1-induced signaling pathways, using specific inhibitors for phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK). Our results indicate that phosphatidylinositol 3-kinase is involved in ectodomain shedding of APP and APLP1, but not APLP2, and that MAPK is involved only in the ectodomain shedding of APLP1.

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    • "Therefore, the sAPP␣ effect may be a rather temporary and secondary response, although we cannot exclude that small sAPP␣ alterations were simply not detectable (due to the ELISA sensitivity), as was the case for sAPP␤ in the GDNF stimulation experiments. Although neurotrophic signaling is generally regarded as positive for the brain, and several growth factors promote the nonamyloidogenic processing of APP by ␣-secretase (Adlerz et al., 2007; Matrone et al., 2008a; Rossner et al., 1998), we revealed here a possibly detrimental side effect of raised GDNF levels. Epidermal growth factor, NGF, and platelet-derived growth factor have also been shown to enhance amyloidogenic processing of APP (Gianni et al., 2003; Zou et al., 2007). "
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    • "Muscarinic receptor activation by carbachol was reported to trigger ADAM17 Thr - 735 phosphorylation and to increase ADAM17 activity , yet without modifying its trafficking to the membrane ( Alfa Cisse et al . 2007 ; Cisse et al . 2011a ) . Insulin and IGF - 1 both can increase the ectodomain shedding of APP in SH - SY5Y cells ( Adlerz et al . 2007 ) , and IGF - 1 also induced PKC - dependent phosphorylation of ADAM17 ( Jacobsen et al . 2010 ) . Other mechanisms of regulation include signaling by ERK1 / 2 and PI3K , which control the pituitary adenylate cyclase - activating polypeptide - stimulated APP a - secretase cleavage ( Kojro et al . 2006 ) . Activation of another kinase p3"
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    ABSTRACT: 'Secretase' is a generic term coined more than 20 years ago to refer to a group of proteases responsible for the cleavage of a vast number of membrane proteins. These endoproteolytic events result in the extracellular or intracellular release of soluble metabolites associated with a broad range of intrinsic physiological functions. α-Secretase refers to the activity targeting the amyloid precursor protein (APP) and generating sAPPα, a soluble extracellular fragment potentially associated with neurotrophic and neuroprotective functions. Several proteases from the a disintegrin and metalloproteinase (ADAM) family, including ADAM10 and ADAM17, have been directly or indirectly associated with the constitutive and regulated α-secretase activities. Recent evidence in primary neuronal cultures indicates that ADAM10 may represent the genuine constitutive α-secretase. Mainly because α-secretase cleaves APP within the sequence of Aβ, the core component of the cerebral amyloid plaques in Alzheimer's disease, α-secretase activation is considered to be of therapeutic value. In this article, we will provide a historical perspective on the characterization of α-secretase and review the recent literature on the identification and biology of the current α-secretase candidates.
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    • "To test this, we transfected wt PS1 and pseudo-phosphorylated PS1 mutant S353/357D PS1 (in which serine residues phosphorylated by GSK3 are substituted with aspartate to mimic phosphorylation state (Uemura et al. 2007)) into MEF PS-/-cells. Transfected cells were treated with insulin to promote ectodomain shedding (Linda et al. 2007) and to inhibit the phosphorylation of wt PS1 (Maesako et al. 2010). APP CTFs band was accumulated in MEF PS-/-cells (Fig. 1A, 1 st lane). "
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