Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease

Abstract

The β-amyloid precursor protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) of Alzheimer's disease. However, the normal function of APP remains largely unknown. This article reviews studies on the structure, expression and post-translational processing of APP, as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms. This article reviews studies on the structure, expression and post-translational processing of β-amyloid precursor protein (APP), as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms.

Keywords: Alzheimer's disease; amyloid precursor protein; growth factor; heparin; neurotrophic; receptor.

Fig. 1

Structure of the amyloid precursor protein (APP) gene, mRNA and protein. (a) The APP gene is located on chromosome 21q21.3. The gene has 18 exons. Differential mRNA splicing of Exons 7,8 (dark grey) can lead to the expression of 695, 751 and 770 amino-acid isoforms. Exons 2 and 15 (light grey) are spliced out in APP639 and L-APP, respectively. (b) Protein structure. APP has an N-terminal signal peptide (SP). The E1 domain has a heparin-binding domain (HBD1), and a copper-binding domain (CuBD); the E2 domain contains a second heparin-binding domain (HBD2). APP751 and APP770 contain a Kunitz protease inhibitor (KPI) and an Ox-2 antigen domain. Between the E2 and Aβ region are two potential N-linked glycosylation sites (CHO). In this region, there is also a potential chondroitin sulphate attachment site that is formed when exon 15 is spliced out. The amino-acid sequence of the Aβ region is shown along with the secretase cleavage sites. The intracellular C-terminal domain contains a YENPTY sorting motif. TMD, transmembrane domain.

Fig. 2

Hypothetical 3-dimensional structure of amyloid precursor protein (APP) based on the following protein data bank files: E1 domain (3KTM), Kunitz protease inhibitor (KPI) domain (1ZJD), E2 domain (3UMK), transmembrane domain (TMD) (2LLM) and intracellular domain (3DXC). A cholesterol molecule is shown in the proposed lipid-binding site in the transmembrane domain. The acidic region and the region between the E2 and Aβ domains are predicated to have little secondary structure.