A NOVEL ROLE FOR RECEPTOR-ASSOCIATED PROTEIN IN SOMATOSTATIN MODULATION - IMPLICATIONS FOR ALZHEIMERS-DISEASE

Receptor-associated protein appears to play an important role in low-d ensity lipoprotein receptor-related protein trafficking. Since ligands for the low-density lipoprotein receptor-related protein have been im plicated in Alzheimer's disease and normal Functioning of this protein is indispensable for central nervous system development, deficient re ceptor-associated protein expression may result in central nervous sys tem alterations. In this study, receptor-associated protein knockout m ice were behaviorally tested and nervous system integrity was assessed via in situ hybridization and immunocytochemical/laser confocal micro scopy methods. Receptor-associated protein knockout mice were found to be cognitively impaired in the Morris water maze compared to controls . In wild-type mice, the receptor-associated protein was found to be h ighly co-expressed with somatostatin in hippocampal and neocortical in hibitory neurons. Receptor-associated protein knockout mice, however, showed a significant decrease in number of somatostatin-expressing neu rons of the CA1 region and somatostatin expression within these neuron s. The decreased number of somatostatin neurons significantly correlat ed with cognitive impairment observed in the receptor-associated prote in knockout mice. These results suggest a novel role for receptor-asso ciated protein in modulating the functioning of somatostatin-producing neurons. Further more, this has implications for Alzheimer's disease pathogenesis, in which altered regulation of both somatostatin and the known low-density lipoprotein receptor-related protein ligands are a consistent finding. (C) 1998 IBRO. Published by Elsevier Science Ltd.