Oligomeric Aβ25–35 induces the tyrosine phosphorylation of PSD-95 by SrcPTKs in rat hippocampal CA1 subfield

Abstract

Purpose

Although amyloid-β (Aβ) is one of the neuropathological hallmarks of Alzheimer’s Disease (AD), the mechanisms of Aβ neurotoxicity remain to be clarified. This study was aimed to evaluate the effect of Aβ on postsynaptic density-95 (PSD-95) tyrosine phosphorylation. Elucidating the regulatory mechanisms underlying it may be a promising therapy in AD.

Methods

Aβ25–35 oligomers (20 μg/rat) were administered intracerebroventricularly in adult male Sprague-Dawley rats. PSD-95 tyrosine phosphorylation was assessed using immunoprecipitation followed by immunoblot analysis. Immunoblot was applied for measuring the protein levels of PSD-95 and β-actin.

Results

Following 3, 7, 14, 21 days after oligomeric Aβ25–35 treatment, the tyrosine phosphorylation of PSD-95 increased significantly, and peaked at 3 days after oligomeric Aβ25–35 treatment in hippocampal CA1 subfield. Src family protein tyrosine kinases (SrcPTKs) specific inhibitor PP2 attenuated the tyrosine phosphorylation of PSD-95 induced by Aβ25–35. Amantadine [N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist], NVP-AAM077 (GluN2A-containing NMDA receptor selective inhibitor) and Ro25-6981 (GluN2B-containing NMDA receptor selective inhibitor) also suppressed the Aβ25–35-induced PSD-95 tyrosine phosphorylation.

Conclusion

These results suggest that Aβ oligomers induce the tyrosine phosphorylation of PSD-95 by SrcPTKs, which is mediated by the activation of GluN2A- and GluN2B-containing NMDA receptors.

Keywords:

• Alzheimer’s disease
• amyloid-β peptide
• PSD-95
• NMDA receptors
• SrcPTKs

Disclosure statement

The authors declare no competing financial interests.

Additional information

Funding

This work was supported by grants from the Science and Technology Project of Xuzhou (KC20132), the National Science Foundation of the Jiangsu Higher Education Institutions (20KJA310010), and the National Natural Science Foundation of China (81100852).