Prof Michal Schwartz
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.

2006 - Autoimmunity, microglia, adult stem cells, neurogenesis, and neurodegenerative diseases
Stem cells are now known to exist in the adult CNS, where they develop into neural cells. The central focuses on mechanisms that maintain and regulate the formation of new neurons in neurogenic niches of the adult brain and the functional relevance of new neuronalpopulations in health and disease. In this connection, relatively few studies have investigated the role of systemic factors that originate or operate outside the brain. Our group showed that local immune cells, controlled by systemic adaptive immune cells, contribute to the maintenance of adult hippocampal neurogenesis and hippocampal-dependent learning abilities 1,2. Our earlier studies showed that T cells which recognize CNS-specific antigens promote CNS maintenance and repair under both acute and chronic neurodegenerative conditions 3,4. They also provided an insight into the mechanism underlying the key role of microglia 5-7 in carrying out immune-mediated therapeutic interventions that are amenable to boosting, such as active vaccination with weak agonists of CNS-antigens 8,9. Effects of the activated microglia are critically determined by their nature and amounts: too little immune activity, as in immune-deficiency syndromes, or too much, as in severe inflammatory diseases, can result in impaired hippocampal neurogenesis 6. After spinal cord injury, T-cell vaccination showed therapeutic synergism with exogenously applied adult neural stem cells 4.

References

1.         Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9, 268-75 (2006).
2.         Kipnis, J., Cohen, H., Cardon, M., Ziv, Y. & Schwartz, M. T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. USA 101, 8180-8185 (2004).
3.         Moalem, G. et al. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5, 49-55 (1999).
4.         Ziv, Y., Avidan, H., Pluchino, S., Martino, G. & Schwartz, M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. submitted (2006).
5.         Butovsky, O. et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116, 905-15 (2006).
6.         Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31, 149-60 (2006).
7.         Butovsky, O., Talpalar, A. E., Ben-Yaakov, K. & Schwartz, M. Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 29, 381-93 (2005).
8.         Schori, H. et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc. Natl. Acad. Sci. U S A 98, 3398-403 (2001).
9.         Butovsky, O. et al. Fighting off Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor-I. Proc Natl Acad Sci U S A In Press (2006).