CRF Binding Protein and Dementia

Corticotrophin releasing factor(CRF) has been implicated in cognitive function and neurologicalillness such as Alzheimer's disease (AD). Evidence includes large decreases in CRF and up-regulationof CRF receptors in brain areas affected in AD. The benefits of postsynaptic CRF agonist therapy maybe outweighed by the angiogenic side effects of CRF. A membrane associated CRF binding protein witha high affinity for CRF and an ability to inactivate CRF has been identified in brain areas associated withAD. Antagonists of CRF-BP may offer a novel means of increasing synaptic CRF in selective brain areaswithout the side effects that would occur with a postsynaptic receptor agonist. The proposed studiesquantify CRF and CRF-BP in postmortem brain samples in AD and age-matched controls; evaluate thecognitive enhancing effects of CRF-BP in animal models of learning, memory and anxiety; and identifynon-peptide leads at the human CRF-BP. The second phase of the proposal will involve optimization ofthe small molecule CRF-BP leads through a directed chemical synthesis program in order to identify novelorally active drugs for cognitive and neuronal deficits seen in AD.