Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß142induced degeneration.
Mol Med Rep
; 24(3)2021 Sep.
Article
em En
| MEDLINE
| ID: mdl-34278489
ABSTRACT
Alzheimer's disease (AD), one of the most common types of chronic neurodegenerative diseases, is pathologically characterized by the formation of amyloid ß (Aß) peptidecontaining plaques and neurofibrillary tangles. Among Aß peptides, Aß142 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aß142induced mitochondrial fission via the phosphorylation of dynaminrelated protein 1 (Drp1) at Ser579. However, whether blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß142induced degeneration remains to be elucidated. Thus, the aim the present study was to examine the effect of mutant Drp1S579A on neurodegeneration and its underlying mechanism. First, the phosphorylationdefect (phosphodefect) mutant, LentiDrp1S579A was constructed. Phosphodefect Drp1S579A expression was detected in primary cultures of mouse cortical neurons infected with LentiDrp1S579A 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 Aß142 significantly decreased dendritic density and length, spine outgrowth and synapse number. As expected, infection of neurons with LentiDrp1S579A efficiently alleviated the inhibitory effect of Aß142 on neurite outgrowth and synapse density. In addition, infection with LentiDrp1S579A abolished the cleavage of caspase3 and apoptosis in neurons exposed to Aß142. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aß142induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Dinaminas
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article