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 APPmRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing

“…1b), i.e. similar to previous findings in normal skin (8). Consistent with these results, WB analysis showed that APP was highly expressed in SK tissues compared with PANST ( Fig.…”

“…APP is an integral type I transmembrane protein, which contains at least 19 exons that are located on chromosome 21 (21q21.2-3) (6, 7). The cDNA sequence of human APP was first cloned from a brain tissue library (6,8). APP is processed by at least 3 proteases, i.e.…”

“…α-, β-and γ-secretases, via the amyloidogenic and nonamyloidogenic pathways (9). In the amyloidogenic path way cleavage by β-secretase (BACE) and γ-secretase releases amyloid-β42 (Aβ42), which plays an important role in early pathological events in early-onset familial AD and sporadic age-related AD (8,10). Moreover, previous studies have shown that other age-related diseases, such as Parkinson's disease and age-related macular degeneration, are accompanied by high levels of expression of APP (11)(12)(13)(14).…”

The Roles of Genetics in Aβ related Alzheimer's Diseases

“…After a long period of time, the Aβ hydrolyzate eventually degrades. Although this had no effect on the generation of Aβ , the Aβ 1-40 level was reduced [70]. In transgenic mice, heterozygous carriers with PSEN-1/R278I mutation express higher level of neurotoxic Aβ 1-43 peptide, thus inhibiting the expression level of normal Aβ 1-40 peptide.…”

Epigenetics in Rare Diseases

“…2.4.2.8; MIM 300800 [22][23][24]) has been reported [25][26][27]. Results of quantification of various APP-mRNA isoforms indicated an epistasis (gene-gene interactions) between mutated Hypoxanthine Phosphoribosyl Transferase 1 (HPRT1) and APP genes.…”