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

Abstract

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.

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Change history

  • 14 June 2018

    The original version of this article unfortunately contained mistake. The old version of Fig. 3 was published.

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Acknowledgements

This work was supported by NHMRC grants (XFZ&YJW) and University President’s Scholarship (NBM).

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Correspondence to Noralyn Basco Mañucat-Tan or Xin-Fu Zhou.

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Mañucat-Tan, N.B., Saadipour, K., Wang, Y. et al. Cellular Trafficking of Amyloid Precursor Protein in Amyloidogenesis Physiological and Pathological Significance. Mol Neurobiol 56, 812–830 (2019). https://doi.org/10.1007/s12035-018-1106-9

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Keywords

  • APP
  • BACE1
  • Cellular trafficking
  • Gamma-secretase
  • Amyloidogenesis