Hyperphosphorylated tau Inflicts Intracellular Stress Responses That Are Mitigated by Apomorphine

Author:

Song Zhenfeng1,Wang Kuang-Wei2,Hagar Hsiao-Tien Chien3,Chen Hong-Ru4,Kuan Chia-Yi5,Zhang Kezhong1,Kuo Min-Hao3ORCID

Affiliation:

1. Wayne State University School of Medicine

2. Michigan State University College of Osteopathic Medicine

3. Michigan State University

4. National Yang Ming Chiao Tung University

5. University of Virginia School of Medicine

Abstract

Abstract Background 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 underlie neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs.Methods 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.Results 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.Conclusion 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.

Publisher

Research Square Platform LLC

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