CORTICOTROPIN-RELEASING FACTOR (CRF), CRF-BINDING PROTEIN (CRF-BP), AND CRF CRF-BP COMPLEX IN ALZHEIMERS-DISEASE AND CONTROL POSTMORTEM HUMAN BRAIN/

In Alzheimer's disease (AD) there are dramatic reductions in human cor ticotropin-releasing factor (hCRF) concentration and reciprocal increa ses in CRF receptor density in the cortex. hCRF-binding protein (hCRF- BP), hCRF/hCRF-BP complex, and ''free'' hCRF were measured in 10 brain regions from control and AD postmortem human tissue. In the control b rains hCRF-BP was heterogenously distributed and levels were at least 10-fold higher on a molar basis than total hCRF levels, suggesting tha t one major role of the binding protein is to limit the actions of hCR F at the hCRF receptors. Concordant with this hypothesis, the percenta ge of total hCRF that was in the bound inactive form ranged from 65 to 90% in most areas examined, with the exception of the caudate and glo bus pallidus where only 15 and 40% were complexed, respectively. hCRF- BP concentrations were similar in the control and AD groups except for Brodmann area (BA) 39 where there was a small but significant decreas e in the AD group Complexed hCRF levels were significantly decreased I n BA 8/BA 9, BA 22, BA 39, nucleus basalis, and globus pallidus in the Alzheimer's group and free hCRF levels were significantly decreased o nly in three brain areas, BA 4, BA 39, and caudate; substantial (40%) but nonsignificant decreases were also noted in BA 8/BA 9 and BA 22. T hese data demonstrate that (1) a large proportion of the total hCRF in human brain is complexed to hCRF-BP and thus unavailable for hCRF rec eptor activation, (2) reductions in total hCRF alone do not necessaril y predict reductions in bioactive free hCRF, and (3) total hCRF levels and hCRF BP levels appear to be the main factors determining the quan tity of bound and free hCRF in human brain.