Recent Advances in Neural Stem Cell Research: How Stem Cells in the Brain Are Altered by a Changing Environment

The expression of immature neuronal markers, which signal the birth of new neurons, was studied in both AD and control hippocampi. Hippocampal western blotting was carried out to detect and identify the following markers: doublecortin (DCX - a microtubule associated marker located in somata and processes of migrating and differentiating neurons), polysialylated neural cell adhesion molecule (PSA-NCAM - a plasma membrane glycoprotein expressed by neuronal progenitors and differentiating neurons and astroglia in response to several different toxic insults), TUC-4 (a marker expressed early in neuronal differentiation in the rat), NeuroD (a basic helix-loop-helix protein expressed during terminal differentiation), NeuN, Calbindin, and actin, the latter to serve as a control.

The resulting banding pattern (i.e. the increased expression of DCX, PSA-NCAM, TUC-4, and NeuroD) in contrast to the stagnant expression of Calbindin and NeuN, both markers for mature neurons, suggested that neurogenesis might be enhanced in the hippocampus of AD patients. Jin et al also demonstrated immunohistochemical evidence for increased neurogenesis in the hippocampi of AD brains, with TUC-4+ and DCX+ cells being localised both to the SGZ and GCL compared to control, which only labelled cells in the SGZ. In particular, compared to healthy control hippocampi, DCX+ cells were identified in the CA1 region of the diseased brains, providing strong evidence for the recruitment of new neurons to a region which is the primary site of hippocampal pathology in AD (Jin, Peel et al., 2004) and one which experiences the most severe neuronal loss. Finally, it was established using double labelling Immunohistochemistry with Hu and PSA-NCAM, that the newly generated TUC-4+ and DCX+ cells were of a neuronal lineage, and not simply expressing characteristic neurogenic markers.

With the resulting increase in expression of neuronal markers in the hippocampi of AD brains and immunocytochemical localisation to known sites of neurogenesis (DG) and AD pathology (CA1), these findings are consistent with earlier studies of increased neurogenesis in response to epilepsy and stroke (Arvidsson et al., 2002; Crespel et al., 2005; Jin, Wang et al., 2006). Consequently, this study has had important implications for hippocampal neurogenesis in response to a chronic neurodegerative insult such as AD, where the hippocampus is selectively and disproportionately targeted. The fact that there exits an apparent compensatory mechanism even in response to AD, a condition which occurs at increasing frequency with advancing age adds support that this inherent plasticity of the brain can be manipulated (Maurice A. Curtis, Faull et al., 2007; Jin, Peel et al., 2004).

Indeed, the recapitulation of hippocampal neurogenesis in an animal model of AD (Jin, Galvan et al., 2004) lends substantial evidence of the hippocampus as a potential therapeutic target. Although no present evidence connects neurogenesis with improved function or slower disease progression in AD (Jin, Peel et al., 2004), there is speculation that NMDA receptor inhibition to enhance dentate neurogenesis might contribute to the antagonists of NDMA receptors such as Memantine, which are currently in use to alleviate AD symptomatology in patients (Jin, Xie, Mao, & Greenberg, 2006). In light of this however, the culmination of evidence from several studies which show an overall down regulation of neurogenesis, with AB impairing proliferation and neuronal differentiation of cultured human and rodent progenitor cells (Haughey, Liu, Nath, Borchard, & Mattson, 2002), means the implications from such studies are somewhat conflicting for AD. Despite this, the demonstration by Becker and colleagues, that immunotherapy against the N terminus of AB stimulated endogenous neurogenesis (Becker, Lavie, & Solomon, 2007), i.e. the accumulation of BrdU by a high number of cells and subsequent co-labelling with NeuN (a marker for mature neurons) is suggestive of anti-amyloid immunotherapy promoting recovery of AB toxicity by partial restoration of neuronal population. The status of neurogenesis in AD thus remains to be hotly debated, primarily due to the probable masking of this effect by AB toxicity on surrounding progenitor cells (Maurice A. Curtis, Faull et al., 2007).

To this extent, there are several possibilities to explain the limited capacity of neurogenesis in disease states. Firstly the extent and rate of cell loss may be too great for neurogenesis to compensate. Secondly the neurons which are generated may fail to successfully integrate into the circuits. Lastly the microenvironment which the disease fosters may be toxic to new neurons. The latter may be resolved or alleviated by administration of growth factors and environment enrichment, two related factors which also result in altered neurogenesis (Jin, Peel et al., 2004; McKay, 2004).

Conclusion

Although the potential usefulness of neurogenesis in the adult human brain remains to be fully delineated, it is clear that after an insult such as ischemia or neurodegeneration, there exists in the brain an inherent mechanism to up regulate progenitor cell proliferation. By increasing SVZ NPC proliferation and migration towards sites of injury, as well as the successful integration of the progenitors into the damaged tissue, future research may improve mortality and quality of life of sufferers of neurodegerative disease. Whether progressive cell loss will continue to occur despite potential therapeutic intervention is a possible future direction of the field (Zhao, Deng, & Gage, 2008).

---

References

Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med, 8(9), 963-970.

Barkho, B. Z., Song, H., Aimone, J. B., Smrt, R. D., Kuwabara, T., Nakashima, K., et al. (2006). Identification of Astrocyte-expressed Factors That Modulate Neural Stem/Progenitor Cell Differentiation. Stem Cells and Development, 15(3), 407-421.

Becker, M., Lavie, V., & Solomon, B. (2007). Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences, 104(5), 1691-1696.

Cattaneo, E., & McKay, R. (1990). Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature, 347(6295), 762-765.

Crespel, A., Rigau, V., Coubes, P., Rousset, M. C., de Bock, F., Okano, H., et al. (2005). Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiology of Disease, 19(3), 436-450.

Curtis, M. A., Eriksson, P. S., & Faull, R. L. M. (2007). PROGENITOR CELLS AND ADULT NEUROGENESIS IN NEURODEGENERATIVE DISEASES AND INJURIES OF THE BASAL GANGLIA. Clinical and Experimental Pharmacology and Physiology, 34(5-6), 528-532.

Curtis, M. A., Faull, R. L. M., & Eriksson, P. S. (2007). The effect of neurodegenerative diseases on the subventricular zone. Nat Rev Neurosci, 8(9), 712-723.

Curtis, M. A., Penney, E. B., Pearson, J., Dragunow, M., Connor, B., & Faull, R. L. M. (2005). The distribution of progenitor cells in the subependymal layer of the lateral ventricle in the normal and Huntington's disease human brain. Neuroscience, 132(3), 777-788.

Emsley, J. G., Mitchell, B. D., Kempermann, G., & Macklis, J. D. (2005). Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Progress in Neurobiology, 75(5), 321-341.

Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., et al. (1998). Neurogenesis in the adult human hippocampus. Nat Med, 4(11), 1313-1317.

Gage, F. H. (2000). Mammalian Neural Stem Cells. Science, 287(5457), 1433.

Gage, F. H. (2002). Neurogenesis in the Adult Brain. J. Neurosci., 22(3), 612-613.

Gao, H., Liu, Y., Lu, S., Xiang, B., & Wang, C. (2006). A Reversible Middle Cerebral Artery Occlusion Model Using Intraluminal Balloon Technique in Monkeys. Journal of Stroke and Cerebrovascular Diseases, 15(5), 202-208.

Haughey, N., Liu, D., Nath, A., Borchard, A., & Mattson, M. (2002). Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid β-peptide. NeuroMolecular Medicine, 1(2), 125-135.

Haughey, N. J., Nath, A., Chan, S. L., Borchard, A. C., Rao, M. S., & Mattson, M. P. (2002). Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. Journal of Neurochemistry, 83(6), 1509-1524.

Jin, K., Galvan, V., Xie, L., Mao, X. O., Gorostiza, O. F., Bredesen, D. E., et al. (2004). Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice. Proceedings of the National Academy of Sciences, 101(36), 13363-13367.

Jin, K., Peel, A. L., Mao, X. O., Xie, L., Cottrell, B. A., Henshall, D. C., et al. (2004). Increased hippocampal neurogenesis in Alzheimer's disease. Proceedings of the National Academy of Sciences, 101(1), 343-347.

Jin, K., Wang, X., Xie, L., Mao, X. O., Zhu, W., Wang, Y., et al. (2006). Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences, 103(35), 13198-13202.

Jin, K., Xie, L., Mao, X. O., & Greenberg, D. A. (2006). Alzheimer's disease drugs promote neurogenesis. Brain Research, 1085(1), 183-188.

Lan Zhang, R., LeTourneau, Y., Gregg, S. R., Wang, Y., Toh, Y., Robin, A. M., et al. (2007). Neuroblast Division during Migration toward the Ischemic Striatum: A Study of Dynamic Migratory and Proliferative Characteristics of Neuroblasts from the Subventricular Zone. J. Neurosci., 27(12), 3157-3162.

Lovell-Badge, R. (2001). The future for stem cell research. Nature, 414(6859), 88-91.

Malcolm R. Alison, R. P. S. F. N. A. W. (2002). An introduction to stem cells. The Journal of Pathology, 197(4), 419-423.

McKay, R. D. (2004). Stem cell biology and neurodegenerative disease. Philosophical Transactions of the Royal Society B: Biological Sciences, 359(1445), 851-856.

Tattersfield, A. S., Croon, R. J., Liu, Y. W., Kells, A. P., Faull, R. L. M., & Connor, B. (2004). Neurogenesis in the striatum of the quinolinic acid lesion model of Huntington's disease. Neuroscience, 127(2), 319-332.

Temple, S. (2001). The development of neural stem cells. Nature, 414(6859), 112-117.

Thored, P., Arvidsson, A., Cacci, E., Ahlenius, H., Kallur, T., Darsalia, V., et al. (2006). Persistent Production of Neurons from Adult Brain Stem Cells During Recovery after Stroke. Stem Cells, 24(3), 739-747.

Thored, P., Wood, J., Arvidsson, A., Cammenga, J., Kokaia, Z., & Lindvall, O. (2007). Long-Term Neuroblast Migration Along Blood Vessels in an Area With Transient Angiogenesis and Increased Vascularization After Stroke. Stroke, 38(11), 3032-3039.

Yamashita, T., Ninomiya, M., Hernandez Acosta, P., Garcia-Verdugo, J. M., Sunabori, T., Sakaguchi, M., et al. (2006). Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum. J. Neurosci., 26(24), 6627-6636.

Yanamoto, H., Nagata, I., Niitsu, Y., Xue, J.-H., Zhang, Z., & Kikuchi, H. (2003). Evaluation of MCAO stroke models in normotensive rats: standardized neocortical infarction by the 3VO technique. Experimental Neurology, 182(2), 261-274.

Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and Functional Implications of Adult Neurogenesis. Cell, 132(4), 645-660.