期刊
CELLS
卷 9, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/cells9112482
关键词
Aβ Alzheimer’ s disease; APP C-terminal fragments; autophagy; SEPTIN5
类别
资金
- Academy of Finland [307866, 315459]
- Sigrid Juselius Foundation
- Strategic Neuroscience Funding of the University of Eastern Finland
- National Institute of Mental Health of the National Institutes of Health [R01MH099660, R01DC015776, R21HD053114, U54HD090260]
- Fundacao para a Ciencia e Tecnologia (FCT) [PD/BD/128390/2017, PD/BD/128091/2016, SFRH/PD/BD/114441/2016]
- Santa Casa da Misericordia de Lisboa [MB37-2017]
- SynaNet [LISBOA-01-0145-FEDER-0073919, 692340]
- FEDER
- POR Lisboa 2020
- Programa Operacional Regional de Lisboa
- PORTUGAL 2020
- Fundacao para a Ciencia e a Tecnologia
- Fundação para a Ciência e a Tecnologia [PD/BD/128091/2016, PD/BD/128390/2017] Funding Source: FCT
Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-beta (A beta) 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 A beta. 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 A beta 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 A beta in neuronal cells.
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