Intensive research on the molecular pathology of Alzheimer's disease (AD) led to the cloning of the amyloid -protein precursor ( PP) and the recognition that altered PPP metabolism and cerebral accumulation of its amyloid -protein (AP) fragment are early and invariant features of AD. In tum, the study of the normal structure and function of this ubiquitously expressed type I integral membrane glycoprotein has led to the cloning of other members of the PPP gene family and the identification of several unusual properties of this mole cule. The study of PP provides a compelling example of research that began with a strictly disease-oriented focus and gave rise to insights into the normal biology of a class of macromolecules.

In this article, I review the salient structural and functional properties of PP and what is currently known about its several alternative trafficking and processing pathways. I attempt to integrate this rapidly emerging information into a hypothetical mechanism for the involvement of PPP metabolism and progressive Ap deposition in the pathogenetic cascade of AD. As is customary for this forum, the review is selective rather than exhaustive, and it presents a critical appraisal of current progress on the biology of PPP and its role in the most common form of age-related mental failure in humans. The study of PPP is providing novel insights into the cell biology of certain cell surface proteins that can serve both as receptors and as secretory precur sors. Conversely, progress in understanding the trafficking and metabolism of such proteins in polarized and nonpolarized cells provides important lessons for students of Alzheimer's disease.