An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation

Department of Medicine, University of Wisconsin-Madison, Veterans Administration Hospital (GRECC 11G), 53705, USA.
The EMBO Journal (Impact Factor: 10.75). 06/2006; 25(9):1997-2006. DOI: 10.1038/sj.emboj.7601062
Source: PubMed

ABSTRACT Aging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75(NTR). An expression pattern in which TrkA predominates in younger animals switches to one in which p75(NTR) predominates in older animals. This TrkA-to-p75(NTR) switch is accompanied by activation of the second messenger ceramide, stabilization of beta-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid beta-peptide (Abeta). Here, we show that the insulin-like growth factor-1 receptor (IGF1-R), the common regulator of lifespan and age-related events in many different organisms, is responsible for the TrkA-to-p75(NTR) switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75(NTR) downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53. We also show that hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of aging, is characterized by early TrkA-to-p75(NTR) switch and increased production of Abeta in the brain.

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    • "iPSCs were differentiated into neurons following established protocols (Johnson et al., 2007; Li and Zhang, 2006; Zhang et al., 2001). SH-SY5Y (human neuroblastoma ) cells were cultured as described before (Costantini et al., 2006). "
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    Neurobiology of Aging 06/2015; Accepted Pub.. DOI:10.1016/j.neurobiolaging.2015.06.021 · 4.85 Impact Factor
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    • "Protein concentration was measured by the bicinchoninic acid method (Pierce). Protein 220 electrophoresis was performed as described before (Costantini et al., 2006; Jonas et al., 2008; 221 (Invitrogen). The following primary antibodies were used: anti-AT1/SLC33A1 (1:500; "
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    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2014; 34(20):6772-89. DOI:10.1523/JNEUROSCI.0077-14.2014 · 6.75 Impact Factor
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    • "In addition, NGF protein secretion is up-regulated by amyloid b administration in glial and neuronal cells (Olivieri et al., 2002; Schulte-Herbrüggen et al., 2007; Bulbarelli et al., 2009). An increase of APP processing occurs in aged animals due to a switch from TrkA to p75 receptors (Costantini et al., 2005a, 2006), and an Ab pathway, directly inducing TrkA phosphorylation and indirectly promoting NGF secretion in cultured neurons, (Bulbarelli et al., 2009) has been recently described. p75 expression is linked to changes occurring in AD (Costantini et al., 2005b,c), probably through its direct binding to Ab 1-42 peptide (Yaar et al., 2002; Susen et al., 2005; Coulson et al., 2006). "
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