AAD  Vol.1 No.3 , December 2012
Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF
ABSTRACT

Brain derived neurotrophic factor (BDNF) levels and signaling via the tyrosine receptor kinase B (TrkB) have been shown to be altered in Alzheimer’s Disease. In addition, it has been reported that the isoforms of TrkB can differentially affect metabolism of amyloid precursor protein (APP). Conversely, Ab, a neurotoxic cleavage product of APP, has been shown to impair TrkB/ BDNF signaling. Therefore, we investigated whether the changes observed in APP metabolism were due to the isoform-specific effects of TrkB on either APP expression, and/or on the expression and activity of ADAM10 and BACE1. Since BDNF levels are decreased in AD, we focused on BDNF independent effects of the TrkB isoforms. We found that TrkB FL increases endogenous APP levels in both HEK293 and SH-SY5Y naive cells. We did not find an increase in ADAM10 activity in HEK293 cells, but an increase in BACE1 levels. Additionally, we have found that TrkB FL is able to increase NFAT3 mediated transcriptional activity and we suggest that this causes transcriptional activation of the BACE1 promoter.


Cite this paper
Ansaloni, S., Leung, B., Dubey, A. and Saunders, A. (2012) Tyrosine kinase receptor B isoforms alter APP and BACE1 endogenous levels independently of BDNF. Advances in Alzheimer's Disease, 1, 93-101. doi: 10.4236/aad.2012.13012.
References
[1]   Alzheimer’s Association (2012) Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 8, 131-168.

[2]   Corbett, A., Smith, J. and Ballard, C. (2012) New and emerging treatments for Alzheimer’s disease. Expert Review of Neurotherapeutics, 12, 535-543. doi:10.1586/ern.12.43

[3]   Benilova, I., Karran, E. and De Strooper, B. (2012) The toxic Abeta oligomer and Alzheimer’s disease: An emperor in need of clothes. Nature Neuroscience, 15, 349- 57. doi:10.1038/nn.3028

[4]   Zhang, F., et al. (2012) Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer’s disease. Journal of Clinical Neuroscience, 19, 946-949.
doi:10.1016/j.jocn.2011.12.022

[5]   Minichiello, L. (2009) TrkB signalling pathways in LTP and learning. Nature Reviews Neuroscience, 10, 850-860. doi:10.1038/nrn2738

[6]   Rothman, S.M., et al. (2012) Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Annals of the New York Academy of Sciences, 1264, 49-63. doi:10.1111/j.1749-6632.2012.06525.x

[7]   Nagahara, A.H. and Tuszynski, M.H. (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nature Reviews Drug Discovery, 10, 209-219. doi:10.1038/nrd3366

[8]   Longo, F.M., et al. (2007) Small molecule neurotrophin receptor ligands: Novel strategies for targeting Alzheimer’s disease mechanisms. Current Alzheimer Research, 4, 503-506.
doi:10.2174/156720507783018316

[9]   Luberg, K., et al. (2010) Human TrkB gene: Novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. Journal of Neurochemistry, 113, 952-964. doi:10.1111/j.1471-4159.2010.06662.x

[10]   Stoilov, P., Castren, E. and Stamm, S. (2002) Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochemical and Biophysical Research Communications, 290, 1054-1065. doi:10.1006/bbrc.2001.6301

[11]   Baxter, G.T., et al. (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB. T2. The Journal of Neuroscience, 17, 2683-2690.

[12]   Wong, J., et al. (2012) Amyloid beta selectively modulates neuronal TrkB alternative transcript expression with implications for Alzheimer’s disease. Neuroscience, 210, 363-374.
doi:10.1016/j.neuroscience.2012.02.037

[13]   Ginsberg, S.D., et al. (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. Journal of Neurochemistry, 97, 475-487. doi:10.1111/j.1471-4159.2006.03764.x

[14]   Poon, W.W., et al. (2009) β-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiology Aging, 32, 821-833.

[15]   Tong, L., et al. (2004) Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. Journal of Neuroscience, 24, 6799-6809. doi:10.1523/JNEUROSCI.5463-03.2004

[16]   Holback, S., Adlerz, L. and Iverfeldt, K. (2005) Increased processing of APLP2 and APP with concomitant formation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells. Journal of Neurochemistry, 95, 1059-1068. doi:10.1111/j.1471-4159.2005.03440.x

[17]   Ruiz-Leon, Y. and Pascual, A. (2001) Brain-derived neurotrophic factor stimulates beta-amyloid gene promoter activity by a Ras-dependent/AP-1-independent mechanism in SH-SY5Y neuroblastoma cells. Journal of Neuroche mistry, 79, 278-285. doi:10.1046/j.1471-4159.2001.00547.x

[18]   Ruiz-Leon, Y. and Pascual, A. (2003) Induction of tyrosine kinase receptor b by retinoic acid allows brain-derived neurotrophic factor-induced amyloid precursor protein gene expression in human SH-SY5Y neuroblastoma cells. Neuroscience, 120, 1019-1026. doi:10.1016/S0306-4522(03)00391-9

[19]   Ruiz-Leon, Y. and Pascual, A. (2004) Regulation of betaamyloid precursor protein expression by brain-derived neurotrophic factor involves activation of both the Ras and phosphatidylinositide 3-kinase signalling pathways. Journal of Neurochemistry, 88, 1010-1018. doi:10.1046/j.1471-4159.2003.02226.x

[20]   Ansaloni, S., et al. (2011) TrkB isoforms differentially affect AICD production though their intracellular functional domains. International Journal of Alzheimer’s Disease, 2011, Article ID: 729382.

[21]   Rajagopal, R., et al., (2004) Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. Journal of Neuroscience, 24, 6650-6658.
doi:10.1523/JNEUROSCI.0010-04.2004

[22]   Schecterson, L.C., et al. (2010) Trk activation in the secretory pathway promotes Golgi fragmentation. Molecular and Cellular Neuroscience, 43, 403-413. doi:10.1016/j.mcn.2010.01.007

[23]   Groth, R.D. and Mermelstein, P.G. (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: A role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. Journal of Neuroscience, 23, 8125-8134.

[24]   Xie, Z., et al. (2007) RNA interference silencing of the adaptor molecules ShcC and Fe65 differentially affect amyloid precursor protein processing and Abeta generation. The Journal of Biological Chemistry, 282, 4318- 4325. doi:10.1074/jbc.M609293200

[25]   Cho, H.J., et al. (2008) Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell, 7, 137- 147. doi:10.1111/j.1474-9726.2007.00360.x

[26]   Manley, K., O’Hara, B.A. and Atwood, W.J. (2008) Nuclear factor of activated T-cells (NFAT) plays a role in SV40 infection. Virology, 372, 48-55. doi:10.1016/j.virol.2007.10.029

[27]   Kamenetz, F., et al. (2003) APP processing and synaptic function. Neuron, 37, 925-937.
doi:10.1016/S0896-6273(03)00124-7

[28]   Hoe, H.S., et al. (2009) The effects of amyloid precursor protein on postsynaptic composition and activity. The Journal of Biological Chemistry, 284, 8495-8506. doi:10.1074/jbc.M900141200

[29]   Caille, I., et al. (2004) Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development, 131, 2173-2181. doi:10.1242/dev.01103

[30]   Obregon, D., et al. (2012) Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. Nature Communications, 3, 777. doi:10.1038/ncomms1781

[31]   Postina, R. (2012) Activation of alpha-secretase cleavage. Journal of Neurochemistry, 120, 46-54. doi:10.1111/j.1471-4159.2011.07459.x

[32]   Turner, S.D., et al. (2007) The NPM-ALK tyrosine kinase mimics TCR signalling pathways, inducing NFAT and AP-1 by RAS-dependent mechanisms. Cell Signal, 19, 740-747. doi:10.1016/j.cellsig.2006.09.007

[33]   Gomes, J.R., et al. (2012) Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons. Journal of Neuroscience, 32, 4610-4622. doi:10.1523/JNEUROSCI.0374-12.2012

[34]   Abdul, H.M., et al. (2009) Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. Journal of Neuroscience, 29, 12957-12969. doi:10.1523/JNEUROSCI.1064-09.2009

[35]   Holler, C.J., et al. (2012) BACE2 expression increases in human neurodegenerative disease. The American Journal of Pathology, 180, 337-350. doi:10.1016/j.ajpath.2011.09.034

 
 
Top