Cellular Trafficking of Amyloid Precursor Protein in Amyloidogenesis Physiological and Pathological Significance

• Published in: Molecular neurobiology Vol. 56; no. 2; pp. 812 - 830
• Main Authors: Mañucat-Tan, Noralyn Basco, Saadipour, Khalil, Wang, Yan-Jiang, Bobrovskaya, Larisa, Zhou, Xin-Fu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2019; Springer Nature B.V
• Subjects: Adaptor proteins; Alzheimer Disease - metabolism; Alzheimer's disease; Amino acids; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - metabolism; Amyloidogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Membrane - metabolism; Cell surface; Enzymes; Humans; Localization; Neurobiology; Neurology; Neurosciences; Neurotrophic factors; Peptides; Phosphorylation; Physiology; Protein transport; Protein Transport - physiology; Proteins; Secretase; β-Site APP-cleaving enzyme 1; BACE1; Gamma-secretase; Amyloidogenesis; APP; Cellular trafficking
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-1106-9

The accumulation of excess intracellular or extracellular amyloid beta (Aβ) is one of the key pathological events in Alzheimer’s disease (AD). Aβ is generated from the cleavage of amyloid precursor protein (APP) by beta secretase-1 (BACE1) and gamma secretase (γ-secretase) within the cells. The endocytic trafficking of APP facilitates amyloidogenesis while at the cell surface, APP is predominantly processed in a non-amyloidogenic manner. Several adaptor proteins bind to both APP and BACE1, regulating their trafficking and recycling along the secretory and endocytic pathways. The phosphorylation of APP at Thr668 and BACE1 at Ser498, also influence their trafficking. Neurotrophins and proneurotrophins also influence APP trafficking through their receptors. In this review, we describe the molecular trafficking pathways of APP and BACE1 that lead to Aβ generation, the involvement of different signaling molecules or adaptor proteins regulating APP and BACE1 subcellular localization. We have also discussed how neurotrophins could modulate amyloidogenesis through their receptors.