Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death
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Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death Mengyu Liu 1 & Dexin Sui 1 & Thomas Dexheimer 2 & Stacy Hovde 1 & Xiexiong Deng 1,3 & Kuang-Wei Wang 1 & Hsin Lian Lin 4 & Hsiao-Tien Chien 1,4 & Hye Kyong Kweon 5 & Nora Sheen Kuo 6 & Christopher A. Ayoub 7 & Daniela Jimenez-Harrison 7 & Philip C. Andrews 5 & Roland Kwok 5,8 & Daniel A Bochar 9 & Jeff Kuret 7 & Jessica Fortin 10 & Yeou-Guang Tsay 4 & Min-Hao Kuo 1 Received: 6 May 2020 / Accepted: 22 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder without a cure or prevention to date. Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments. Animal studies demonstrated the pathogenic role of hyperphosphorylated tau. Understanding how abnormal phosphorylation renders a normal tau prone to form toxic fibrils is key to delineating molecular pathology and to developing efficacious drugs for AD. Production of a tau bearing the disease-relevant hyperphosphorylation and molecular characters is a pivotal step. Here, we report the preparation and characterization of a recombinant hyperphosphorylated tau (p-tau) with strong relevance to disease. P-tau generated by the PIMAX approach resulted in phosphorylation at multiple epitopes linked to the progression of AD neuropathology. In stark contrast to unmodified tau that required an aggregation inducer, and which had minimal effects on cell functions, p-tau formed inducer-free fibrils that triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at submicromolar concentrations. P-tau-induced apoptosis was suppressed by inhibitors for reactive oxygen species. Hyperphosphorylation apparently caused rapid formation of a disease-related conformation. In both aggregation and cytotoxicity, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with an increased propensity for fibrillization. These characters of p-tau are consistent with the emerging view that hyperphosphorylation causes tau to become an aggregation-prone and cytotoxic species that underlies diffusible pathology in AD and other tauopathies. Our results further suggest that p-tau affords a feasible tool for Alzheimer’s disease mechanistic and drug discovery studies. Keywords Alzheimer’s disease . Tauopathy . Hyperphosphorylated tau . Neurofibrillary tangle
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02034-w) contains supplementary material, which is available to authorized users. * Min-Hao Kuo [email protected] 1
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Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA
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Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI, USA
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Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
Center for Molecular Neurobiology, Department of Molecular B
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