Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aβ1‑42‑induced degeneration.

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, Aβ1–42 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aβ1–42-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 Aβ1–42-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 Aβ1–42 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 Aβ1–42. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aβ1–42-induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.