IN-VIVO REGULATION OF AMYLOID PRECURSOR PROTEIN SECRETION IN RAT NEOCORTEX BY CHOLINERGIC ACTIVITY

The proteolytic cleavage of the amyloid precursor protein (APP) has be en shown to be modulated through specific muscarinic receptor activati on in vitro in both transfected cell lines and native brain slices, wh ereas a demonstration of receptor-mediated control of APP processing u nder in vivo conditions is still lacking, To simulate alterations in m uscarinic receptor stimulation in vivo, we have (i) specifically reduc ed the cortical cholinergic innervation in rats using partial immunole sions with 192IgG-saporin: and (ii) restored cholinergic function in l esioned rats by transplantation of nerve growth factor producing fibro blasts. While total APP levels in cortical homogenates were unaffected by cholinergic deafferentation, we observed a significant reduction i n the abundance of secreted APP and a concomitant increase in membrane -bound APP, These changes were reversed in immunolesioned rats with ne rve growth factor-producing fibroblasts, There was a strong positive c orrelation between the ratio of secreted APP to membrane-bound APP and the activity of choline acetyltransferase and M1 muscarinic acetylcho line receptor density (measured by [H-3]pirenzepine binding) in experi mental groups, Additionally, we observed a transient decrease in the r atio of cortical APP transcripts containing the Kunitz protease inhibi tor domain (APP 770 and APP 751) versus APP 695 in rats with cholinerg ic hypoactivity, The data presented suggest that cortical APP processi ng is under basal forebrain cholinergic control, presumably mediated t hrough M1 muscarinic acetylcholine receptors on cholinoceptive cortica l target cells.