Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease
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.