DISPLACEMENT OF CORTICOTROPIN-RELEASING FACTOR FROM ITS BINDING-PROTEIN AS A POSSIBLE TREATMENT FOR ALZHEIMERS-DISEASE

In Alzheimer's disease (AD) there are dramatic reductions in the conte nt of corticotropin releasing factor (CRF)(1-4), reciprocal increases in CRF receptors(1,2), and morphological abnormalities in CRF neurons( 5) in affected brain areas. Cognitive impairment in AD patients is ass ociated with a lower cerebrospinal fluid concentration of CRF(6), whic h is known to induce increases in learning and memory in rodents(7-9). This suggests that CRF deficits contribute to cognitive impairment. T he 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 receptors(13), provides the potential for improving learning and memory without stress effect s of CRF receptor agonists(14). Here we show that ligands that dissoci ate CRF from CRF-BP increase brain levels of 'free CRF' in AD to contr ol levels and show cognition-enhancing properties in models of learnin g and memory in animals without the characteristic stress effects of C RF receptor agonists.