PMID- 33203136 OWN - NLM STAT- MEDLINE DCOM- 20210630 LR - 20210630 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 9 IP - 11 DP - 2020 Nov 15 TI - Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Abeta. LID - 10.3390/cells9112482 [doi] LID - 2482 AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-beta (Abeta) 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 beta-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 Abeta. 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 Abeta 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 Abeta in neuronal cells. FAU - Marttinen, Mikael AU - Marttinen M AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Ferreira, Catarina B AU - Ferreira CB AD - Instituto de Medicina Molecular-Joao Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal. FAU - Paldanius, Kaisa M A AU - Paldanius KMA AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Takalo, Mari AU - Takalo M AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Natunen, Teemu AU - Natunen T AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Makinen, Petra AU - Makinen P AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Leppanen, Luukas AU - Leppanen L AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Leinonen, Ville AU - Leinonen V AUID- ORCID: 0000-0002-4282-4687 AD - Institute of Clinical Medicine-Neurosurgery, University of Eastern Finland, 70210 Kuopio, Finland. AD - Neurology of Neuro Center Kuopio University Hospital, 70210 Kuopio, Finland. FAU - Tanigaki, Kenji AU - Tanigaki K AD - Research Institute, Shiga Medical Center, Shiga 524-8524, Japan. FAU - Kang, Gina AU - Kang G AD - 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. FAU - Hiroi, Noboru AU - Hiroi N AD - 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. FAU - Soininen, Hilkka AU - Soininen H AUID- ORCID: 0000-0002-2785-9937 AD - Institute of Clinical Medicine-Neurology, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Rilla, Kirsi AU - Rilla K AUID- ORCID: 0000-0002-7862-5727 AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Haapasalo, Annakaisa AU - Haapasalo A AUID- ORCID: 0000-0003-0959-2957 AD - A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland. FAU - Hiltunen, Mikko AU - Hiltunen M AUID- ORCID: 0000-0003-3566-4096 AD - Institute of Biomedicine, University of Eastern Finland, 70210 Kuopio, Finland. LA - eng GR - R01 DC015776/DC/NIDCD NIH HHS/United States GR - R01 MH099660/MH/NIMH NIH HHS/United States GR - R21 HD053114/HD/NICHD NIH HHS/United States GR - U54 HD090260/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201115 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Amyloid beta-Peptides) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Cell Cycle Proteins) RN - 0 (Peptide Fragments) RN - EC 3.6.1.- (SEPTIN5 protein, human) RN - EC 3.6.1.- (Sept5 protein, mouse) RN - EC 3.6.1.- (Septins) SB - IM MH - Amyloid beta-Peptides/*metabolism MH - Amyloid beta-Protein Precursor/*metabolism MH - Animals MH - Autophagy/*physiology MH - Brain/metabolism MH - Cell Cycle Proteins/genetics/*metabolism MH - Endocytosis/physiology MH - Humans MH - Mice MH - Mice, Knockout MH - Neurodegenerative Diseases/metabolism MH - Neurons/metabolism MH - Peptide Fragments/metabolism MH - Protein Transport/physiology MH - Septins/genetics/*metabolism PMC - PMC7696542 OTO - NOTNLM OT - APP C-terminal fragments OT - Alzheimer's disease OT - Abeta OT - SEPTIN5 OT - autophagy COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2020/11/19 06:00 MHDA- 2021/07/01 06:00 PMCR- 2020/11/01 CRDT- 2020/11/18 01:02 PHST- 2020/09/17 00:00 [received] PHST- 2020/11/05 00:00 [revised] PHST- 2020/11/10 00:00 [accepted] PHST- 2020/11/18 01:02 [entrez] PHST- 2020/11/19 06:00 [pubmed] PHST- 2021/07/01 06:00 [medline] PHST- 2020/11/01 00:00 [pmc-release] AID - cells9112482 [pii] AID - cells-09-02482 [pii] AID - 10.3390/cells9112482 [doi] PST - epublish SO - Cells. 2020 Nov 15;9(11):2482. doi: 10.3390/cells9112482.