Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ<sub>1‑42</sub>‑induced degeneration

Xu,Dan; Yang,Ping; Yang,Zhang-Jian; Li,Qiu-Gen; Ouyang,Ye-Tong; Yu,Ting; Shangguan,Jian-Hui; Wan,Yu-Ying; Jiang,Li-Ping; Qu,Xin-Hui; Han,Xiao-Jian

doi:10.3892/mmr.2021.12296

September-2021 Volume 24 Issue 3

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September-2021 Volume 24 Issue 3

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Article Open Access

Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ_1‑42‑induced degeneration

Authors:
- Dan Xu
- Ping Yang
- Zhang-Jian Yang
- Qiu-Gen Li
- Ye-Tong Ouyang
- Ting Yu
- Jian-Hui Shangguan
- Yu-Ying Wan
- Li-Ping Jiang
- Xin-Hui Qu
- Xiao-Jian Han
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Affiliations: Institute of Geriatrics, Affiliated People's Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Neurology, Affiliated People's Hospital of Nanchang University, Jiangxi 330006, P.R. China, Department of Pharmacology, School of Pharmaceutical Science, Nanchang University, Jiangxi 330006, P.R. China, Department of Intra‑Hospital Infection Management, The Second Affiliated Hospital of Nanchang University, Jiangxi 330006, P.R. China

Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 657
|
Published online on: July 15, 2021

https://doi.org/10.3892/mmr.2021.12296
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Abstract

Alzheimer's disease (AD), one of the most common types of chronic neurodegenerative diseases, is pathologically characterized by the formation of amyloid β (Aβ) peptide‑containing plaques and neurofibrillary tangles. Among Aβ peptides, Aβ_1‑42 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aβ_1‑42‑induced mitochondrial fission via the phosphorylation of dynamin‑related protein 1 (Drp1) at Ser579. However, whether blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ_1‑42‑induced degeneration remains to be elucidated. Thus, the aim the present study was to examine the effect of mutant Drp1‑S579A on neurodegeneration and its underlying mechanism. First, the phosphorylation‑defect (phospho‑defect) mutant, Lenti‑Drp1‑S579A was constructed. Phospho‑defect Drp1‑S579A expression was detected in primary cultures of mouse cortical neurons infected with Lenti‑Drp1‑S579A using western blotting and it was found to successfully attenuate the phosphorylation of endogenous Drp1 at Ser579. In primary neuronal cultures, the neuronal processes were evaluated under microscopy. Treatment with 10 µM Aβ1‑42 significantly decreased dendritic density and length, spine outgrowth and synapse number. As expected, infection of neurons with Lenti‑Drp1‑S579A efficiently alleviated the inhibitory effect of Aβ_1‑42 on neurite outgrowth and synapse density. In addition, infection with Lenti‑Drp1‑S579A abolished the cleavage of caspase‑3 and apoptosis in neurons exposed to Aβ_1‑42. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aβ_1‑42‑induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.

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