Pathological Tau From Alzheimer’s Brain Induces Site-Specific Hyperphosphorylation and SDS- and Reducing Agent-Resistant Aggregation of Tau in vivo

• Published in: Frontiers in aging neuroscience Vol. 11; p. 34
• Main Authors: Miao, Jin, Shi, Ruirui, Li, Longfei, Chen, Feng, Zhou, Yan, Tung, Yunn Chyn, Hu, Wen, Gong, Cheng-Xin, Iqbal, Khalid, Liu, Fei
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 05.03.2019; Frontiers Media S.A
• Subjects: AD P-tau; Aging; Alzheimer's disease; Brain research; Dephosphorylation; Developmental disabilities; Hippocampus; hyperphosphorylation of tau; Kinases; Laboratory animals; Molecular weight; Neurodegenerative diseases; Neurofibrillary tangles; Neuroscience; Pathology; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; propagation of tau pathology; Protein phosphatase; Proteins; Seeds; tau pathology; Tau protein; Toxicity; Transgenic mice; New York; United States > US; China; hyperphosphorylation of tau; tau pathology; AD P-tau; Alzheimer’s disease; propagation of tau pathology
• ISSN: 1663-4365; 1663-4365
• DOI: 10.3389/fnagi.2019.00034

Neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau are a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Hyperphosphorylation of tau is responsible for its loss of normal physiological function, gain of toxicity and its aggregation to form NFTs. Injection of misfolded tau seeds into mouse brain induces tau aggregation, but the nature of tau phosphorylation in pathologic tau seeded pathology is unclear. In the present study, we injected hyperphosphorylated and oligomeric tau isolated from AD brain (AD P-tau) into hippocampus of human tau transgenic mice and found that in addition to tau aggregation/pathology, tau was hyperphosphorylated at Ser202/Thr205, Thr212, Ser214, Thr217, Ser262, and Ser422 in AD P-tau injected hippocampus and at Ser422 in the contralateral hippocampus and in the ipsilateral cortex. AD P-tau-induced AD-like high molecular weight aggregation of tau that was SDS- and reducing agent-resistant and site-specifically hyperphosphorylated in the ipsilateral hippocampus. There were no detectable alterations in levels of tau phosphatases or tau kinases in AD P-tau-injected brains. Furthermore, we found that hyperphosphorylated tau was easier to be captured by AD P-tau and that aggregated tau was more difficult to be dephosphorylated than the non-aggregated tau by protein phosphatase 2A (PP2A). Based on these findings, we speculate that AD P-tau seeds hyperphosphorylated tau to form aggregates, which resist to the dephosphorylation by PP2A, resulting in hyperphosphorylation and pathology of tau.