Dataset Information

SIRT7 Deficiency Protects against Aβ₄₂-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

ABSTRACT: Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ₄₂, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD. However, the involvement of SIRT7 in AD pathogenesis is not known. Here, we demonstrate that SIRT7 mRNA expression is increased in the cortex, entorhinal cortex, and prefrontal cortex of AD patients. We also found that Aβ₄₂ treatment rapidly increased NADPH oxidase 4 (NOX4) expression at the post-transcriptional level, and induced reactive oxygen species (ROS) production and apoptosis in neuronal SH-SY5Y cells. In contrast, SIRT7 knockdown inhibited Aβ₄₂-induced ROS production and apoptosis by suppressing the upregulation of NOX4. Collectively, these findings suggest that the inhibition of SIRT7 may play a beneficial role in AD pathogenesis through the regulation of ROS production.

SUBMITTER: Mizutani H

PROVIDER: S-EPMC9408927 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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SIRT7 Deficiency Protects against Aβ<sub>42</sub>-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Mizutani Hironori H Sato Yoshifumi Y Yamazaki Masaya M Yoshizawa Tatsuya T Ando Yukio Y Ueda Mitsuharu M Yamagata Kazuya K

International journal of molecular sciences 20220812 16

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ<sub>42</sub>, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD. However, the involvement of SIRT7 in AD pathogene ...[more]

PMID: 36012298

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Project description:Aggregated amyloid beta (Aβ) is widely reported to cause neuronal dystrophy and toxicity through multiple pathways: oxidative stress, disrupting calcium homeostasis, and cytoskeletal dysregulation. The neuro-cytoskeleton is a dynamic structure that reorganizes to maintain cell homeostasis in response to varying soluble and physical cues presented from the extracellular matrix (ECM). Due this relationship between cell health and the ECM, we hypothesize that amyloid toxicity may be directly influenced by physical changes to the ECM (stiffness and dimensionality) through mechanosensitive pathways, and while previous studies demonstrated that Aβ can distort focal adhesion signaling with pathological consequences, these studies do not address the physical contribution from a physiologically relevant matrix. To test our hypothesis that physical cues can adjust Aβ toxicity, SH-SY5Y human neuroblastoma and primary human cortical neurons were plated on soft and stiff, 2D polyacrylamide matrices or suspended in 3D collagen gels. Each cell culture was exposed to escalating concentrations of oligomeric or fibrillated Aβ(1-42) with MTS viability and lactate dehydrogenase toxicity assessed. Actin restructuring was further monitored in live cells by atomic force microscopy nanoindentation, and our results demonstrate that increasing either matrix stiffness or exposure to oligomeric Aβ promotes F-actin polymerization and cell stiffening, while mature Aβ fibrils yielded no apparent cell stiffening and minor toxicity. Moreover, the rounded, softer mechanical phenotype displayed by cells plated onto a compliant matrix also demonstrated a resilience to oligomeric Aβ as noted by a significant recovery of viability when compared to same-dosed cells plated on traditional tissue culture plastic. This recovery was reproduced pharmacologically through inhibiting actin polymerization with cytochalasin D prior to Aβ exposure. These studies indicate that the cell-ECM interface can modify amyloid toxicity in neurons and the matrix-mediated pathways that promote this protection may offer unique targets in amyloid pathologies like Alzheimer's disease.

Dataset Information

SIRT7 Deficiency Protects against Aβ₄₂-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Publications

SIRT7 Deficiency Protects against Aβ<sub>42</sub>-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Similar Datasets

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Dataset Information

SIRT7 Deficiency Protects against Aβ42-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Publications

SIRT7 Deficiency Protects against Aβ<sub>42</sub>-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

SIRT7 Deficiency Protects against Aβ₄₂-Induced Apoptosis through the Regulation of NOX4-Derived Reactive Oxygen Species Production in SH-SY5Y Cells.