Regulation of APP processing. Potential for the therapeutical reduction of brain amyloid burden

The role of brain amyloid in the pathogenesis of Alzheimer's disease (AD) is discussed controversially, but combined genetic and biochemical evidence points to a central role of the gene encoding the amyloid precursor APP in at least some forms of AD. This article proposes that preventing brain amyloid formation is a rational concept for drug treatment of AD. We suggest that pharmacologically active ligands for specific cell surface receptor subtypes--normally stimulated by neurotransmitters, growth factors, and cytokines--constitute a class of chemicals that might be useful to accelerate processing of APP into non-amyloidogenic, and biologically active, derivatives. This class of agents includes muscarinic m1 and m3 agonists, serotoninergic 5-HT2a and 5-HT2c agonists, glutamatergic mGluR1 agonists, as well as agonists for bradykinin and vasopressin receptors.