Abstract
Accumulation of β-amyloid peptide (Aβ) is regarded as a primary cause of Alzheimer’s disease (AD). Aβ is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aβ production. Sorting receptors, such as SorLA, convey subcellular targeting of APP. Dysfunction of SorLA, and likely of the related receptors SorCS1 and SorCS3, cause AD. Nevertheless, disease progression could also provoke altered expression of the receptors. Here, we assessed if Aβ plaque formation promotes altered expression of SorLA, SorCS1 and SorCS3. We analyzed transcript levels during aging and after amyloidosis in brain areas characterized by early amyloid plaque formation in an AD mouse model (APPPS1) and wild types. We observed stable expression levels during aging (1–12 months). After plaque formation, SorCS1 and SorLA expression were markedly reduced in the frontal cerebral cortex and to a minor extent in the hippocampus, whereas SorCS3 expression was solely reduced in the frontal cerebral cortex. Our results indicate that disease progression, associated with Aβ accumulation, can negatively regulate expression of the receptors.
Acknowledgments
Funding was provided by Alzheimer Forschung Initiative e.V. (AFI) to S.K. and G.H.
References
Andersen, O.M., Reiche, J., Schmidt, V., Gotthardt, M., Spoelgen, R., Behlke, J., von Arnim, C.A.F., Breiderhoff, T., Jansen, P., Wu, X., et al. (2005). Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. U.S.A. 102, 13461–13466.10.1073/pnas.0503689102Search in Google Scholar PubMed PubMed Central
Andersen, O.M., Schmidt, V., Spoelgen, R., Gliemann, J., Behlke, J., Galatis, D., McKinstry, W.J., Parker, M.W., Masters, C.L., Hyman, B.T., et al. (2006). Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11. Biochemistry 45, 2618–2628.10.1021/bi052120vSearch in Google Scholar PubMed
Andersen, O.M., Rudolph, I.M., and Willnow, T.E. (2016). Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol. 132, 653–66510.1007/s00401-016-1615-4Search in Google Scholar PubMed PubMed Central
Bluthgen, N., van Bentum, M., Merz, B., Kuhl, D., and Hermey, G. (2017). Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo. Sci. Rep. 7, 45101.10.1038/srep45101Search in Google Scholar PubMed PubMed Central
Borchelt, D.R., Thinakaran, G., Eckman, C.B., Lee, M.K., Davenport, F., Ratovitsky, T., Prada, C.M., Kim, G., Seekins, S., Yager, D., et al. (1996). Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.10.1016/S0896-6273(00)80230-5Search in Google Scholar
Brunholz, S., Sisodia, S., Lorenzo, A., Deyts, C., Kins, S., and Morfini, G. (2012). Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells. Exp. Brain Res. 217, 353–364.10.1007/s00221-011-2870-1Search in Google Scholar PubMed PubMed Central
Bustin, S.A., Benes, V., Garson, J.A., Hellemans, J., Huggett, J., Kubista, M., Mueller, R., Nolan, T., Pfaffl, M.W., Shipley, G.L., et al. (2009). The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55, 611–622.10.1373/clinchem.2008.112797Search in Google Scholar PubMed
Caglayan, S., Takagi-Niidome, S., Liao, F., Carlo, A.S., Schmidt, V., Burgert, T., Kitago, Y., Fuchtbauer, E.M., Fuchtbauer, A., Holtzman, D.M., et al. (2014). Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci. Transl. Med. 6, 223ra20.10.1126/scitranslmed.3007747Search in Google Scholar PubMed
Dickey, C.A., Loring, J.F., Montgomery, J., Gordon, M.N., Eastman, P.S., and Morgan, D. (2003). Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein+presenilin-1 transgenic mice. J. Neurosci. 23, 5219–5226.10.1523/JNEUROSCI.23-12-05219.2003Search in Google Scholar PubMed PubMed Central
Dineley, K.T., Westerman, M., Bui, D., Bell, K., Ashe, K.H., and Sweatt, J.D. (2001). Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal α7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer’s disease. J. Neurosci. 21, 4125–4133.10.1523/JNEUROSCI.21-12-04125.2001Search in Google Scholar PubMed PubMed Central
Dodson, S.E., Gearing, M., Lippa, C.F., Montine, T.J., Levey, A.I., and Lah, J.J. (2006). LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease. J. Neuropathol. Exp. Neurol. 65, 866–872.10.1097/01.jnen.0000228205.19915.20Search in Google Scholar PubMed PubMed Central
Dodson, S.E., Andersen, O.M., Karmali, V., Fritz, J.J., Cheng, D.M., Peng, J.M., Levey, A.I., Willnow, T.E., and Lah, J.J. (2008). Loss of LR11/SORLA enhances early pathology in a mouse model of amyloidosis: evidence for a proximal role in Alzheimer’s disease. J. Neurosci. 28, 12877–12886.10.1523/JNEUROSCI.4582-08.2008Search in Google Scholar PubMed PubMed Central
Eggert, S., Gonzalez, A.C., Thomas, C., Schilling, S., Schwarz, S.M., Tischer, C., Adam, V., Strecker, P., Schmidt, V., Willnow, T.E., et al. (2018a). Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA. Cell. Mol. Life Sci. 75, 301–322.10.1007/s00018-017-2625-7Search in Google Scholar PubMed
Eggert, S., Thomas, C., Kins, S., and Hermey, G. (2018b). Trafficking in Alzheimer’s disease: modulation of APP transport and processing by the transmembrane proteins LRP1, SorLA, SorCS1c, Sortilin, and Calsyntenin. Mol. Neurobiol. 55, 5809–5829.10.1007/s12035-017-0806-xSearch in Google Scholar PubMed
El Bitar, F., Qadi, N., Al Rajeh, S., Majrashi, A., Abdulaziz, S., Majrashi, N., Al Inizi, M., Taher, A., and Al Tassan, N. (2019). Genetic study of Alzheimer’s disease in Saudi population. J. Alzheimers Dis. 67, 231–242.10.3233/JAD-180415Search in Google Scholar PubMed
Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., and Gillespie, F. (1995). Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527.10.1038/373523a0Search in Google Scholar PubMed
Grupe, A., Li, Y., Rowland, C., Nowotny, P., Hinrichs, A.L., Smemo, S., Kauwe, J.S., Maxwell, T.J., Cherny, S., Doil, L., et al. (2006). A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am. J. Hum. Genet. 78, 78–88.10.1086/498851Search in Google Scholar PubMed PubMed Central
Haass, C., Kaether, C., Thinakaran, G., and Sisodia, S. (2012). Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. 2, a006270.10.1101/cshperspect.a006270Search in Google Scholar PubMed PubMed Central
Hardy, J.A. and Higgins, G.A. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185.10.1126/science.1566067Search in Google Scholar PubMed
He, Y., Fang, Z., and Yu, G. (2012). Sortilin-related VPS10 domain containing receptor 1 and Alzheimer’s disease-associated allelic variations preferentially exist in female or type 2 diabetes mellitus patients in southern Han Chinese. Psychogeriatrics 12, 215–225.10.1111/j.1479-8301.2012.00405.xSearch in Google Scholar PubMed
Hermans-Borgmeyer, I., Hampe, W., Schinke, B., Methner, A., Nykjaer, A., Susens, U., Fenger, U., Herbarth, B., and Schaller, H.C. (1998). Unique expression pattern of a novel mosaic receptor in the developing cerebral cortex. Mech. Dev. 70, 65–76.10.1016/S0925-4773(97)00177-9Search in Google Scholar
Hermey, G. (2009). The Vps10p-domain receptor family. Cell. Mol. Life Sci. 66, 2677–2689.10.1007/s00018-009-0043-1Search in Google Scholar PubMed
Hermey, G., Schaller, H.C., and Hermans-Borgmeyer, I. (2001). Transient expression of SorCS in developing telencephalic and mesencephalic structures of the mouse. Neuroreport 12, 29–32.10.1097/00001756-200101220-00014Search in Google Scholar PubMed
Hermey, G., Plath, N., Hubner, C.A., Kuhl, D., Schaller, H.C., and Hermans-Borgmeyer, I. (2004). The three sorCS genes are differentially expressed and regulated by synaptic activity. J. Neurochem. 88, 1470–1476.10.1046/j.1471-4159.2004.02286.xSearch in Google Scholar PubMed
Hermey, G., Mahlke, C., Gutzmann, J.J., Schreiber, J., Bluthgen, N., and Kuhl, D. (2013). Genome-wide profiling of the activity-dependent hippocampal transcriptome. PLoS ONE 8, e76903.10.1371/journal.pone.0076903Search in Google Scholar PubMed PubMed Central
Hermey, G., Schmidt, N., Bluhm, B., Mensching, D., Ostermann, K., Rupp, C., Kuhl, D., and Kins, S. (2015). SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport. J. Neurochem. 135, 60–75.10.1111/jnc.13221Search in Google Scholar PubMed
Kanaki, T., Bujo, H., Hirayama, S., Tanaka, K., Yamazaki, H., Seimiya, K., Morisaki, N., Schneider, W.J., and Saito, Y. (1998). Developmental regulation of LR11 expression in murine brain. DNA Cell Biol. 17, 647–657.10.1089/dna.1998.17.647Search in Google Scholar PubMed
Kitago, Y., Nagae, M., Nakata, Z., Yagi-Utsumi, M., Takagi-Niidome, S., Mihara, E., Nogi, T., Kato, K., and Takagi, J. (2015). Structural basis for amyloidogenic peptide recognition by sorLA. Nat. Struct. Mol. Biol. 22, 199–206.10.1038/nsmb.2954Search in Google Scholar PubMed
Klinger, B., Sieber, A., Fritsche-Guenther, R., Witzel, F., Berry, L., Schumacher, D., Yan, Y., Durek, P., Merchant, M., Schafer, R., et al. (2013). Network quantification of EGFR signaling unveils potential for targeted combination therapy. Mol. Syst. Biol. 9, 673.10.1038/msb.2013.29Search in Google Scholar PubMed PubMed Central
Lane, R.F., Raines, S.M., Steele, J.W., Ehrlich, M.E., Lah, J.A., Small, S.A., Tanzi, R.E., Attie, A.D., and Gandy, S. (2010). Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-β metabolism: evidence for involvement of SorL1 and the retromer complex. J. Neurosci. 30, 13110–13115.10.1523/JNEUROSCI.3872-10.2010Search in Google Scholar PubMed PubMed Central
Mehmedbasic, A., Christensen, S.K., Nilsson, J., Rutschi, U., Gustafsen, C., Poulsen, A.S.A., Rasmussen, R.W., Fjorback, A.N., Larson, G., and Andersen, O.M. (2015). SorLA Complement-type repeat domains protect the amyloid precursor protein against processing. J. Biol. Chem. 290, 3359–3376.10.1074/jbc.M114.619940Search in Google Scholar PubMed PubMed Central
Murer, M.G., Yan, Q., and Raisman-Vozari, R. (2001). Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog. Neurobiol. 63, 71–124.10.1016/S0301-0082(00)00014-9Search in Google Scholar
Musiek, E.S. and Holtzman, D.M. (2015). Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat. Neurosci. 18, 800–806.10.1038/nn.4018Search in Google Scholar PubMed PubMed Central
Ni, H., Xu, M., Zhan, G.L., Fan, Y., Zhou, H., Jiang, H.Y., Lu, W.H., Tan, L., Zhang, D.F., Yao, Y.G., et al. (2018). The GWAS risk genes for depression may be actively involved in Alzheimer’s disease. J. Alzheimers Dis. 64, 1149–1161.10.3233/JAD-180276Search in Google Scholar PubMed
Nicolas, G., Charbonnier, C., Wallon, D., Quenez, O., Bellenguez, C., Grenier-Boley, B., Rousseau, S., Richard, A.C., Rovelet-Lecrux, A., Le Guennec, K., et al. (2016). SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol. Psychiatry 21, 831–836.10.1038/mp.2015.121Search in Google Scholar PubMed
Nunes, A.F., Amaral, J.D., Lo, A.C., Fonseca, M.B., Viana, R.J., Callaerts-Vegh, Z., D’Hooge, R., and Rodrigues, C.M. (2012). TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice. Mol. Neurobiol. 45, 440–454.10.1007/s12035-012-8256-ySearch in Google Scholar PubMed
Oetjen, S., Mahlke, C., Hermans-Borgmeyer, I., and Hermey, G. (2014). Spatiotemporal expression analysis of the growth factor receptor SorCS3. J. Comp. Neurol. 522, 3386–3402.10.1002/cne.23606Search in Google Scholar PubMed
Paban, V., Loriod, B., Villard, C., Buee, L., Blum, D., Pietropaolo, S., Cho, Y.H., Gory-Faure, S., Mansour, E., Gharbi, A., et al. (2017). Omics analysis of mouse brain models of human diseases. Gene 600, 90–100.10.1016/j.gene.2016.11.022Search in Google Scholar PubMed
Pfaffl, M.W., Horgan, G.W., and Dempfle, L. (2002). Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30, e36.10.1093/nar/30.9.e36Search in Google Scholar PubMed PubMed Central
Plath, N., Ohana, O., Dammermann, B., Errington, M.L., Schmitz, D., Gross, C., Mao, X., Engelsberg, A., Mahlke, C., Welzl, H., et al. (2006). Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52, 437–444.10.1016/j.neuron.2006.08.024Search in Google Scholar PubMed
Radde, R., Bolmont, T., Kaeser, S.A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M.E., Jaggi, F., Wolburg, H., Gengler, S., et al. (2006). Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946.10.1038/sj.embor.7400784Search in Google Scholar PubMed PubMed Central
Reitz, C., Tokuhiro, S., Clark, L.N., Conrad, C., Vonsattel, J.P., Hazrati, L.N., Palotas, A., Lantigua, R., Medrano, M., Z Jiménez-Velázquez, I., et al. (2011). SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer’s disease risk. Ann. Neurol. 69, 47–64.10.1002/ana.22308Search in Google Scholar PubMed PubMed Central
Reitz, C., Tosto, G., Vardarajan, B., Rogaeva, E., Ghani, M., Rogers, R.S., Conrad, C., Haines, J.L., Pericak-Vance, M.A., Fallin, M.D., et al. (2013). Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). Transl. Psychiatry 3, e256.10.1038/tp.2013.13Search in Google Scholar PubMed PubMed Central
Rohe, M., Carlo, A.S., Breyhan, H., Sporbert, A., Militz, D., Schmidt, V., Wozny, C., Harmeier, A., Erdmann, B., Bales, K.R., et al. (2008). Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J. Biol. Chem. 283, 14826–14834.10.1074/jbc.M710574200Search in Google Scholar PubMed
Rohe, M., Synowitz, M., Glass, R., Paul, S.M., Nykjaer, A., and Willnow, T.E. (2009). Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J. Neurosci. 29, 15472–15478.10.1523/JNEUROSCI.3960-09.2009Search in Google Scholar PubMed PubMed Central
Rupp, N.J., Wegenast-Braun, B.M., Radde, R., Calhoun, M.E., and Jucker, M. (2011). Early onset amyloid lesions lead to severe neuritic abnormalities and local, but not global neuron loss in APPPS1 transgenic mice. Neurobiol. Aging 32, 2324.e2321–2326.10.1016/j.neurobiolaging.2010.08.014Search in Google Scholar PubMed
Savas, J.N., Ribeiro, L.F., Wierda, K.D., Wright, R., DeNardo-Wilke, L.A., Rice, H.C., Chamma, I., Wang, Y.Z., Zemla, R., Lavallee-Adam, M., et al. (2015). The sorting receptor SorCS1 regulates trafficking of neurexin and AMPA receptors. Neuron 87, 764–780.10.1016/j.neuron.2015.08.007Search in Google Scholar PubMed PubMed Central
Scherzer, C.R., Offe, K., Gearing, M., Rees, H.D., Fang, G.F., Heilman, C., Schaller, C., Bujo, H., Levey, A.I., and Lah, J.J. (2004). Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch. Neurol. Chicago 61, 1200–1205.10.1001/archneur.61.8.1200Search in Google Scholar PubMed
Small, S.A. and Gandy, S. (2006). Sorting through the cell biology of Alzheimer’s disease: intracellular pathways to pathogenesis. Neuron 52, 15–31.10.1016/j.neuron.2006.09.001Search in Google Scholar PubMed PubMed Central
Tanila, H. (2017). The role of BDNF in Alzheimer’s disease. Neurobiol. Dis. 97, 114–118.10.1016/j.nbd.2016.05.008Search in Google Scholar PubMed
Wang, H.F., Yu, J.T., Zhang, W., Wang, W., Liu, Q.Y., Ma, X.Y., Ding, H.M., and Tan, L. (2012). SORCS1 and APOE polymorphisms interact to confer risk for late-onset Alzheimer’s disease in a Northern Han Chinese population. Brain Res. 1448, 111–116.10.1016/j.brainres.2012.01.067Search in Google Scholar PubMed
Willnow, T.E., Petersen, C.M., and Nykjaer, A. (2008). VPS10P-domain receptors – regulators of neuronal viability and function. Nat. Rev. Neurosci. 9, 899–909.10.1038/nrn2516Search in Google Scholar PubMed
Xie, F., Xiao, P., Chen, D., Xu, L., and Zhang, B. (2012). miRDeepFinder: a miRNA analysis tool for deep sequencing of plant small RNAs. Plant Mol. Biol. 80, 75–84.10.1007/s11103-012-9885-2Search in Google Scholar PubMed
Xu, W., Xu, J., Wang, Y., Tang, H., Deng, Y., Ren, R., Wang, G., Niu, W., Ma, J., Wu, Y., et al. (2013). The genetic variation of SORCS1 is associated with late-onset Alzheimer’s disease in Chinese Han population. PLoS ONE 8, e63621.10.1371/journal.pone.0063621Search in Google Scholar PubMed PubMed Central
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