Effects of Neurotrophic Factors on the Secretion and Metabolism of the Alzheimer Amyloid Precursor

The Alzheimer disease (AD) and Down syndrome (DS) neuritic plaques consist of a central amyloid core surrounded by a spherical cluster of dystrophic degenerating and regenerating neuntes. The main component of the plaque amyloid is a small protein (βA4 protein) which derives from a larger amyloid precursor protein (APP). It has been proposed that the neuritic regeneration associated with the neuritic plaques takes place in the presence of a milieu of neurotrophic factors. It is, therefore, important to determine the effect of various neurotrophic factors on the metabolism of APP. Using antisera against specific APP sequences we determined that, in PC 12 cell cultures, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) stimulate the secretion of at least two different APP isoforms, both of which derive from the Kunitz protease inhibitor (KPI) containing βAPP and both of which differ in their degree of glycosylation. In addition, bFGF induced the appearance of a novel APP isoform in the human astrocytoma cell line HBT 14. Immunoblots using specific monoclonal and polyclonal antibodies indicated that the NGFsecreted APP form is cleaved from its precursor within the first ten amino acids that immediately follow the transmembrane region. A similarly reactive APP form has been detected in human cerebrospinal fluid. These results suggest that normal metabolism of APP involves cleavage within the βA4 protein sequence, thus preventing amyloid formation. Furthermore, they suggest that production of the amyloid protein in AD and DS may involve a defect in the enzymic system involved in the cleavage of the secreted forms of APP. This could cause degradation of the precursor through alternative and possibly nonspecific pathways, thus initiating the process leading to amyloid deposition.