Processing of Alzheimer Aβ-Amyloid Precursor Protein: Cell Biology, Regulation, and Role in Alzheimer Disease

This chapter discusses the nature and regulation of pathways for the cellular processing of amyloid precursor protein (APP) that are extensively characterized. Recent data demonstrate that soluble Aβ-amyloid is released from various cells and tissues in the course of normal cellular metabolism. Studies of APP catabolic intermediates and soluble Aβ-amyloid in sporadic- Alzheimer disease (AD) tissues and fluids have not provided specific SAD-associated changes in APP metabolism. However, studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to enhanced generation or aggregability of Aβ-amyloid, consistent with a pathogenic role in AD. In addition, genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and familial Alzheimer disease (FAD). It remains to be elucidated which, if any, of these rare genetic causes of AD is most relevant to the understanding of typical, common specific-AD.