Generation and Role of Calpain-Cleaved 17-kDa Tau Fragment in Acute Ischemic Stroke

• Published in: Molecular neurobiology Vol. 58; no. 11; pp. 5814 - 5825
• Main Authors: Chen, Ying-Da, Huang, Po-Yuan, Chiang, Chien-Sung, Huang, Yi-Shuian, Tang, Sung-Chun
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2021; Springer Nature B.V
• Subjects: Acute Disease; Alzheimer's disease; Animals; Biomedical and Life Sciences; Biomedicine; Brain Chemistry; Brain Ischemia - metabolism; Calpain; Calpain - metabolism; Cell Biology; Cell death; Cell Shape; Cells, Cultured; Cerebral blood flow; Dipeptides - pharmacology; Ectopic expression; Enzyme Activation; Genes, Reporter; Glucose; Humans; Infarction, Middle Cerebral Artery - metabolism; Ischemia; MAP Kinase Signaling System; Mass spectroscopy; Nerve Tissue Proteins - metabolism; Neurobiology; Neurodegenerative diseases; Neurology; Neurons - metabolism; Neurons - ultrastructure; Neurosciences; Neurotoxicity; Oxygen; Peptide Fragments - metabolism; Primary Cell Culture; Protein Processing, Post-Translational; Proteolysis; Rats; Recombinant Proteins - metabolism; Reperfusion; Stroke; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tau proteolysis; Calpain; Neuron; Ischemic stroke; OGD/R
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02519-2

Stroke is the leading cause of permanent disability and death in the world. The therapy for acute stroke is still limited due to the complex mechanisms underlying stroke-induced neuronal death. The generation of a 17-kDa neurotoxic tau fragment was reported in Alzheimer’s disease but it has not been well studied in stroke. In this study, we observed the accumulation of 17-kDa tau fragment in cultured primary neurons and media after oxygen-glucose deprivation/reperfusion (OGD/R) treatment that could be diminished by the presence of a calpain inhibitor. This calpain-mediated proteolytic tau fragment was also detected in brain tissues from middle cerebral artery occlusion–injured rats and acute ischemic stroke patients receiving strokectomy, and human plasma samples collected within 48 h after the onset of stroke. The mass spectrometry analysis of this 17-kDa fragment identified 2 peptide sequences containing 195–224 amino acids of tau, which agrees with the previously reported tau 45-230 or tau 125-230 as the calpain-cleaved tau fragment. Ectopic expression of tau 45-230 -GFP but not tau 125-230 -GFP in cultured neurons induced the formation of tortuous processes without evident cell death. In summary, the 17-kDa tau fragment is a novel stroke biomarker and may play a pathophysiological role to affect post-stroke neuronal health.