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: 10.43). 06/2006; 25(9):1997-2006. DOI: 10.1038/sj.emboj.7601062
Source: PubMed


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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    ABSTRACT: p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases. Here, we report that the amyloid precursor protein (APP) intracellular domain (AICD), which results from the processing of the APP, regulates translation of p44 through a cap-independent mechanism that requires direct binding to the second internal ribosome entry site (IRES) of the p53 mRNA. We also report that AICD associates with nucleolin, an already known IRES-specific trans-acting factor that binds with p53 IRES elements and regulates translation of p53 isoforms. The potential biological impact of our findings was assessed in a mouse model of Alzheimer's disease. In conclusion, our study reveals a novel aspect of AICD and p53/p44 biology and provides a possible molecular link between APP, p44, and tau. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 06/2015; Accepted Pub.(10). DOI:10.1016/j.neurobiolaging.2015.06.021 · 5.01 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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    ABSTRACT: The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.
    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 · 6.34 Impact Factor
    • "The signaling pathway that controls the level of TrkA and p75NTR downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53.[46] The hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of ageing, is characterized by early TrkA-to-p75NTR switch and increased production of Aβ in the brain.[46] "
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    ABSTRACT: Ageing, also called as senescence, is one of the most complex, intrinsic, biological processes of growing older and resulting into reduced functional ability of the organism. Telomerase, environment, low calorie diets, free radicals, etc., are all believed to affect this ageing process. A number of genetic components of ageing have been identified using model organisms. Genes, mainly the sirtuins, regulate the ageing speed by indirection and controlling organism resistance to damages by exogenous and endogenous stresses. In higher organisms, ageing is likely to be regulated, in part, through the insulin/insulin-like growth factor 1 pathway. Besides this, the induction of apoptosis in stem and progenitor cells, increased p53 activity, and autophagy is also thought to trigger premature organismal ageing. Ageing has also been shown to upregulate expression of inflammatory mediators in mouse adipose tissue. The understanding of pathophysiology of ageing over the past few years has posed tremendous challenges for the development of anti-ageing medicine for targeted therapy. Future research areas must include targeted role of systemic inflammatory markers such as C-reactive protein and interleukin 6 and other biochemical and genetic studies including gene signaling pathways, gene microarray analysis, gene modulation, gene therapy, and development of animal/human models for potential therapeutic measures and evaluations.
    Indian Journal of Dermatology 11/2011; 56(6):615-21. DOI:10.4103/0019-5154.91816
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