Hyperphosphorylated Tau Inflicts Intracellular Stress Responses that Are Mitigated by Apomorphine

Zhenfeng Song, Kuang Wei Wang, Hsiao Tien Chien Hagar, Hong Ru Chen, Chia Yi Kuan, Kezhong Zhang*, Min Hao Kuo*

*此作品的通信作者

研究成果: Article同行評審

摘要

Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer’s disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson’s disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer’s disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer’s disease drug discovery.

原文English
頁(從 - 到)2653-2671
頁數19
期刊Molecular Neurobiology
61
發行號5
DOIs
出版狀態Published - 5月 2024

指紋

深入研究「Hyperphosphorylated Tau Inflicts Intracellular Stress Responses that Are Mitigated by Apomorphine」主題。共同形成了獨特的指紋。

引用此