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Catabolism and Anabolism of Amyloid-β

  • Shoko Hashimoto
  • Per Nilsson
  • Takaomi C. SaidoEmail author
Chapter

Abstract

According to the amyloid cascade hypothesis, the initial elevation of amyloid β-peptide (Aβ) level is the primary trigger of Alzheimer’s disease (AD). The steady-state levels of Aβ are determined by the balance of the production and clearance of Aβ. Ιn familial AD, an imbalance in Aβ kinetics arises from the abnormal generation of Aβ due to mutations in the secretases, which cleave Aβ from the amyloid precursor protein (APP), or in APP itself. However, the large majority of AD is sporadic AD (SAD), which lacks a strong genetic component. In SAD, inactivations of Aβ degradation systems might instead be the cause of the disease. We previously identified neprilysin (NEP) as the major Aβ-degrading enzyme. Importantly, NEP declines in the human brain with aging, which may contribute to the increased Aβ pathology. Therefore, the up-regulation of NEP activity in the brain represents a potential therapy for the prevention of AD. To that end, we recently developed a system to overexpress NEP throughout the brain using an newly designed adeno-associated viral vector carrying the NEP gene (AAV-NEP). In addition to the Aβ-degrading enzymes, we recently found that autophagy plays an important role in Aβ metabolism. Specifically, autophagy influences the intracellular sorting and secretion of Aβ. Intriguingly, autophagy deficiency induces intracellular Aβ accumulation, which enhances autophagy deficiency-induced neurodegeneration. This result indicates that intracellular Aβ might be toxic. Indeed, Aβ clearance systems are potential therapeutic targets in AD, to prevent the disease via a treatment already in early stages.

Keywords

APP BACE1 γ-secretase Neprilysin Autophagy Aβ transport APP knock-in model mice 

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Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Shoko Hashimoto
    • 1
  • Per Nilsson
    • 1
  • Takaomi C. Saido
    • 1
    Email author
  1. 1.Laboratory for Proteolytic NeuroscienceRIKEN Brain Science InstituteSaitamaJapan

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