Hyperphosphorylated Tau Inflicts Intracellular Stress Responses that Are Mitigated by Apomorphine.

Autor: Song Z; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA., Wang KW; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA., Hagar HC; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA., Chen HR; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22903, USA.; Present address: Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan, 112304., Kuan CY; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, 22903, USA., Zhang K; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA. kzhang@med.wayne.edu., Kuo MH; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA. kuom@msu.edu.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 May; Vol. 61 (5), pp. 2653-2671. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1007/s12035-023-03689-x
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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