Abstract
IN Alzheimer's disease (AD) there are dramatic reductions in the content of corticotropin releasing factor (CRF)1–4, reciprocal increases in CRF receptors1,2, and morphological abnormalities in CRF neurons5 in affected brain areas. Cognitive impairment in AD patients is associated with a lower cerebrospinal fluid concentration of CRF6, which is known to induce increases in learning and memory in rodents7–9. This suggests that CRF deficits contribute to cognitive impairment. The identification in post-mortem brain of CRF-binding protein (CRF-BP)10,11, a high-affinity binding protein that inactivates CRF, and the differential distribution of CRF-BP12 and CRF receptors13, provides the potential for improving learning and memory without stress effects of CRF receptor agonists14. Here we show that ligands that dissociate CRF from CRF-BP increase brain levels of 'free CRF' in AD to control levels and show cognition-enhancing properties in models of learning and memory in animals without the characteristic stress effects of CRF receptor agonists.
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References
De Souza, E. B. Hosp. Pract. 23, 59–71 (1988).
De Souza, E. B. et al. Nature 319, 591–595 (1986).
Bissette, G. et al. J. Am. med. Ass. 254, 3067–3069 (1985).
Whitehouse, P. J. et al. Neurology 37, 905–909 (1987).
Powers, R. E. et al. Synapse 1, 405–410 (1987).
Pomara, N. et al. Biol. Psychiat. 26, 500–504 (1989).
Koob, G. F. & Bloom, F. E. Fedn Proc. 44, 259–262 (1985).
Liang, K. C. & Lee, E. H. Y. Psychopharmacology 96, 232–236 (1988).
Diamant, M. & de Wied, D. Neuroendocrinology 57, 1071–1081 (1993).
Behan, D. P. et al. Ann. N. Y. Acad. Sci. 697, 1–8 (1993).
Potter, E. et al. Nature 349, 423–426 (1991).
Potter, E. et al. Proc. natn. Acad. Sci. U.S.A. 89, 4192–4196 (1992).
De Souza, E. B. et al. J. Neurosci. 5, 3189–3203 (1985).
Koob, G. F. et al. in Corticotropin-Releasing Factor (eds Chadwick, D. J., Marsh, J. & Ackrill, K.) 277–295 (Wiley, Chichester, UK, 1993).
Linton, E. A., Wolfe, C. D. A., Behan, D. P. & Lowry, P. J. Clin. Endocr. 28, 315–324 (1988).
Orth, D. N. & Mount, C. D. Biochem. biophys. Res. Commun. 143, 411–417 (1987).
Suda, T. et al. J. clin. Endocr. Metab. 67, 1278–1283 (1988).
McKhann, G. et al. Neurology 34, 939–944 (1984).
Khachaturian, Z. S. Archs Neurol. 42, 1097–1105 (1985).
Sutton, S. W. et al. Endocrinology 136, 1097–1102 (1995).
Stewart, C. A. & Morris, R. G. M. in Behavioral Neuroscience (ed. Saghal, A.) 107–122 (IRL, Oxford Univ. Press, 1993).
Pellow, S. et al. J. Neurosci. Meth. 14, 149–167 (1985).
De Souza, E. B. A. Rep. med. Chem. 25, 215–224 (1990).
Chrousos, G. P. & Gold, P. W. J. Am. med. Ass. 267, 1244–1252 (1992).
Chen, R., Lewis, K. A., Perrin, M. H. & Vale, W. W. Proc. natn. Acad. Sci. U.S.A. 90, 8967–8971 (1993).
De Souza, E. B. J. Neurosci. 7, 88–100 (1987).
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Behan, D., Heinrichs, S., Troncoso, J. et al. Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease. Nature 378, 284–287 (1995). https://doi.org/10.1038/378284a0
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DOI: https://doi.org/10.1038/378284a0
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