| Autor: |
Marttinen M; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Ferreira CB; Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal., Paldanius KMA; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Takalo M; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Natunen T; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Mäkinen P; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Leppänen L; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Leinonen V; Institute of Clinical Medicine-Neurosurgery, University of Eastern Finland, 70210 Kuopio, Finland.; Neurology of Neuro Center Kuopio University Hospital, 70210 Kuopio, Finland., Tanigaki K; Research Institute, Shiga Medical Center, Shiga 524-8524, Japan., Kang G; Department of Pharmacology, Department of Integrative and Systems Physiology, Department of Cell Systems and Anatomy, Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 77030, USA., Hiroi N; Department of Pharmacology, Department of Integrative and Systems Physiology, Department of Cell Systems and Anatomy, Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX 77030, USA., Soininen H; Institute of Clinical Medicine-Neurology, University of Eastern Finland, 70210 Kuopio, Finland., Rilla K; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland., Haapasalo A; A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland., Hiltunen M; Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. |
| Abstrakt: |
Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells. |
