AAD> Vol.2 No.4, December 2013

Phosphorylated low-density lipoprotein receptor-related protein 6 is prevalent in hippocampal progenitor cells and circuits of aged human hippocampus

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ABSTRACT

Wnt signaling has been implicated in Alzheimer’s disease (AD) pathogenesis, but no studies have described Wnt signaling in aging brain. Phosphorylation of the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (Lrp6), is a sensitive indicator of Wnt ligand-receptor interaction and canonical Wnt signaling. We report that in aged human temporal lobe, the phospho-Lrp6 (pLrp6) epitope localizes to neurons in the entorhinal cortex (EC), the dentate gyrus (DG), and the hippocampal formation, especially in the CA3 field. Activated Lrp6 is detected in neuronal soma and in neuronal processes, particularly in the mossy fiber terminals in the stratum lucidum of CA3. These three regions and their connectivity represent the afferent arm of the major hippocampal circuit. In the DG, cells positive for pLrp6 include Type 1 and Type 2 hippocampal progenitor cells. Overall, these data indicate regional Wnt receptor activation in the human hippocampus that is most prominent in the cells comprising the afferent arm of the major hippocampal circuit that is associated with learning and memory functions. These findings are consistent with data from rodent studies which suggest an important role for Wnts in adult neurogenesis in the human DG. We speculate that Wnt signaling may be an activity-dependent trophic influence in the hippocampus.

Cite this paper

Sullivan, C. , Elliott-Bryant, R. , Kanesa-Thasan, A. , McKee, A. , Fine, R. , Wells, J. and Morin, P. (2013) Phosphorylated low-density lipoprotein receptor-related protein 6 is prevalent in hippocampal progenitor cells and circuits of aged human hippocampus. Advances in Alzheimer's Disease, 2, 126-131. doi: 10.4236/aad.2013.24017.

References

[1] Knoth, R., Singec, I., Ditter, M., Pantazis, G., Capetian, P., Meyer, R.P., Horvat, V., Volk, B. and Kempermann G. (2010) Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years, PLoS One, 5, Article ID: e8809. http://dx.doi.org/10.1371/journal.pone.0008809
[2] Boekhoorn, K., Joels, M. and Lucassen, P.J. (2006) Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiology of Disease, 24, 1-14. http://dx.doi.org/10.1016/j.nbd.2006.04.017
[3] Jin, K., Peel, A.L., Mao, X.O., Xie, L., Cottrell, B.A., Henshall, D.C. and Greenberg, D.A. (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 101, 343-347. http://dx.doi.org/10.1073/pnas.2634794100
[4] Lee, S.M., Tole, S., Grove, E. and McMahon, A.P. (2000) A local Wnt-3a signal is required for development of the mammalian hippocampus. Development, 127, 457-467.
[5] Zhou, C.J., Borello, U., Rubenstein, J.L. and Pleasure, S.J. (2006) Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway. Neuroscience, 142, 1119-1131. http://dx.doi.org/10.1016/j.neuroscience.2006.07.007
[6] Lie, D.C., Colamarino, S.A., Song, H.J., Desire, L., Mira, H., Consiglio, A., Lein, E.S., Jessberger, S., Lansford, H., Dearie, A.R. and Gage, F.H. (2005) Wntsignalling regulates adult hippocampal neurogenesis. Nature, 437, 1370-1375. http://dx.doi.org/10.1038/nature04108
[7] Munji, R.N., Choe, Y., Li, G., Siegenthaler, J.A. and Pleasure, S.J. (2011) Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. The Journal of Neuroscience, 31, 1676-1687. http://dx.doi.org/10.1523/JNEUROSCI.5404-10.2011
[8] MacDonald, B.T., Yokota, C., Tamai, K., Zeng, X. and He, X. (2008) Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. The Journal of Biological Chemistry, 283, 16115-16123. http://dx.doi.org/10.1074/jbc.M800327200
[9] Piao, S., Lee, S.H., Kim, H., Yum, S., Stamos, J.L., Xu, Y., Lee, S.J., Lee, J., Oh, S., Han, J.K., Park, B.J., Weis, W.I. and Ha, N.C. (2008) Direct inhibition of GSK3beta by the phosphorylated cyto-plasmic domain of LRP6 in Wnt/ beta-catenin signaling. PLoS One, 3, Article ID: e4046.
[10] Squire, L.R., Stark, C.E. and Clark, R.E. (2004) The medial temporal lobe. Annual Review of Neuroscience, 27, 279-306. http://dx.doi.org/10.1146/annurev.neuro.27.070203.144130
[11] Sullivan, C.P., Jay, A.G., Stack, E.C., Pakaluk, M., Wadlinger, E., Fine, R.E., Wells, J.M. and Morin, P.J. (2011) Retromer disruption promotes amyloidogenic APP processing. Neurobiology of Disease, 43, 338-345. http://dx.doi.org/10.1016/j.nbd.2011.04.002
[12] Sullivan, C.P., Berg, E.A., Elliott-Bryant, R., Fishman, J.B., McKee, A.C., Morin, P.J., Shia, M.A. and Fine, R.E. (2011) Pyroglutamate-Aβ 3 and 11 colocalize in amyloid plaques in Alzheimer’s disease cerebral cortex with pyroglutamate-Aβ 11 forming the central core. Neuroscience Letters, 505, 109-112.
[13] Zeng, X., Tamai, K., Doble, B., Li, S., Huang, H., Habas, R., Okamura, H., Woodgett, J. and He, X. (2005) A dualkinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 438, 873-877. http://dx.doi.org/10.1038/nature04185
[14] Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A. and Gage, F.H. (1998) Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313-1317. http://dx.doi.org/10.1038/3305
[15] Zhao, C., Deng, W. and Gage, F.H. (2008) Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645-660. http://dx.doi.org/10.1016/j.cell.2008.01.033
[16] L’Episcopo, F., Serapide, M.F., Tirolo, C., Testa, N., Caniglia, S., Morale, M.C., Pluchino, S. and Marchetti, B. (2011) A Wnt1 regulated Frizzled-1/beta-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuronastrocyte crosstalk: Therapeutical relevance for neuron survival and neuro- protection. Molecular Neurodegeneration, 6, 49. http://dx.doi.org/10.1186/1750-1326-6-49
[17] White, B.D., Nathe, R.J., Maris, D.O., Nguyen, N.K., Good- son, J.M., Moon, R.T. and Horner, P.J. (2010) Beta-catenin signaling increases in proliferating NG2+ progenytors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells, 28, 297-307.
[18] Liebner, S. and Plate, K.H. (2010) Differentiation of the brain vasculature: The answer came blowing by the Wnt. Journal of Angiogenesis Research, 2, 1.
[19] Budnik, V. and Salinas, P.C. (2011) Wnt signaling during synaptic development and plasticity. Current Opinion in Neurobiology, 21, 151-159. http://dx.doi.org/10.1016/j.conb.2010.12.002
[20] Farias, G.G., Alfaro, I.E., Cerpa, W., Grabowski, C.P., Godoy, J.A., Bonansco, C. and Inestrosa, N.C. (2009) Wnt-5a/ JNK signaling promotes the clustering of PSD-95 in hippocampal neurons. Journal of Biological Chemistry, 284, 15857-15866. http://dx.doi.org/10.1074/jbc.M808986200
[21] Korkut, C., Ataman, B., Ramachandran, P., Ashley, J., Barria, R., Gherbesi, N. and Budnik, V. (2009), Trans-synaptic transmission of vesicular Wnt signals through Evi/ Wntless. Cell, 139, 393-404. http://dx.doi.org/10.1016/j.cell.2009.07.051
[22] Speese, S.D. and Budnik, V. (2007) Wnts: Up-and-coming at the synapse. Trends in Neurosciences, 30, 268-275. http://dx.doi.org/10.1016/j.tins.2007.04.003
[23] Iqbal, K. and Grundke-Iqbal, I. (2011) Opportunities and challenges in developing Alzheimer disease therapeutics. Acta Neuropathologica, 122, 543-549. http://dx.doi.org/10.1007/s00401-011-0878-z
[24] Yassa, M.A., Mattfeld, A.T., Stark, S.M. and Stark, C.E. (2011) Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 108, 8873-8878. http://dx.doi.org/10.1073/pnas.1101567108

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