Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ
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 acc...
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MDPI AG
2020-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/11/2482 |
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| author | Mikael Marttinen Catarina B. Ferreira Kaisa M. A. Paldanius Mari Takalo Teemu Natunen Petra Mäkinen Luukas Leppänen Ville Leinonen Kenji Tanigaki Gina Kang Noboru Hiroi Hilkka Soininen Kirsi Rilla Annakaisa Haapasalo Mikko Hiltunen |
| author_facet | Mikael Marttinen Catarina B. Ferreira Kaisa M. A. Paldanius Mari Takalo Teemu Natunen Petra Mäkinen Luukas Leppänen Ville Leinonen Kenji Tanigaki Gina Kang Noboru Hiroi Hilkka Soininen Kirsi Rilla Annakaisa Haapasalo Mikko Hiltunen |
| author_sort | Mikael Marttinen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T14:49:43Z |
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| id | doaj.art-5647ef2d3b1d45008a721e15b1ef2b35 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T14:49:43Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-5647ef2d3b1d45008a721e15b1ef2b352023-11-20T21:02:14ZengMDPI AGCells2073-44092020-11-01911248210.3390/cells9112482Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of AβMikael Marttinen0Catarina B. Ferreira1Kaisa M. A. Paldanius2Mari Takalo3Teemu Natunen4Petra Mäkinen5Luukas Leppänen6Ville Leinonen7Kenji Tanigaki8Gina Kang9Noboru Hiroi10Hilkka Soininen11Kirsi Rilla12Annakaisa Haapasalo13Mikko Hiltunen14Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstituto de Medicina Molecular—João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, PortugalInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Clinical Medicine–Neurosurgery, University of Eastern Finland, 70210 Kuopio, FinlandResearch Institute, Shiga Medical Center, Shiga 524-8524, JapanDepartment 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, USADepartment 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, USAInstitute of Clinical Medicine–Neurology, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandA.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, 70210 Kuopio, FinlandAlzheimer’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.https://www.mdpi.com/2073-4409/9/11/2482AβAlzheimer’s diseaseAPP C-terminal fragmentsautophagySEPTIN5 |
| spellingShingle | Mikael Marttinen Catarina B. Ferreira Kaisa M. A. Paldanius Mari Takalo Teemu Natunen Petra Mäkinen Luukas Leppänen Ville Leinonen Kenji Tanigaki Gina Kang Noboru Hiroi Hilkka Soininen Kirsi Rilla Annakaisa Haapasalo Mikko Hiltunen Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ Cells Aβ Alzheimer’s disease APP C-terminal fragments autophagy SEPTIN5 |
| title | Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ |
| title_full | Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ |
| title_fullStr | Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ |
| title_full_unstemmed | Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ |
| title_short | Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ |
| title_sort | presynaptic vesicle protein septin5 regulates the degradation of app c terminal fragments and the levels of aβ |
| topic | Aβ Alzheimer’s disease APP C-terminal fragments autophagy SEPTIN5 |
| url | https://www.mdpi.com/2073-4409/9/11/2482 |
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