The human β-amyloid precursor protein: biomolecular and epigenetic aspects.

Abstract

Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age <65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age >65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APP-mRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.