Abstract
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.
Highlights
The main theoretical concept in Alzheimer’s disease (AD) is the amyloid cascade hypothesis, postulating that amyloid-β (Aβ) deposition in the brain is a primary driver of AD pathogenesis, impairing synaptic efficacy, and causes calcium dyshomeostasis, inflammation, oxidative stress, as well as tau hyperphosphorylation and the formation of neurofibrillary tangles (NFTs) at specific brain regions [1]
Several SEPTINs have been identified to take part in biological processes that are aberrantly affected in AD pathogenesis, such as autophagy and synaptic plasticity [7]
Studies addressing the potential role of SEPTINs in AD pathogenesis remains sparse
Summary
The main theoretical concept in Alzheimer’s disease (AD) is the amyloid cascade hypothesis, postulating that amyloid-β (Aβ) deposition in the brain is a primary driver of AD pathogenesis, impairing synaptic efficacy, and causes calcium dyshomeostasis, inflammation, oxidative stress, as well as tau hyperphosphorylation and the formation of neurofibrillary tangles (NFTs) at specific brain regions [1]. SEPTINs are a conserved family of 13 GTP-binding proteins highly expressed in the brain and are involved in processes, such as the regulation of formation, growth, and stability of axons and dendrites; synaptic plasticity; and autophagy, all of which have been identified to be affected during AD pathogenesis [7,8]. Our previous studies showed that SEPTIN5 downregulation led to altered APP processing in human embryonic kidney cells by reducing the levels of soluble. We set the goal to assess the effects of SEPTIN5 downregulation on APP processing and the generation of Aβ in different in vitro and in vivo neuronal models. Our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in vitro and in vivo
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