Neurotoxicity of oligomers of phosphorylated Tau protein carrying tauopathy-associated mutation is inhibited by prion protein

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Nieznanska, Hanna¹  Boyko, Solomiia^1,3  Dec, Robert²  Redowicz, Maria Jolanta¹  Dzwolak, Wojciech²  Nieznanski, Krzysztof¹ 

[1] Polish Acad Sci, Nencki Inst Expt Biol, 3 Pasteur Str, PL-02093 Warsaw, Poland

[2] Univ Warsaw, Fac Chem, Biol & Chem Res Ctr, 1 Pasteur Str, PL-02093 Warsaw, Poland

[3] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA

关键词: Alzheimer's disease;    Amyloid;    Protein oligomerization;    Protein aggregation;    Tauopathies;    PrPC;   

DOI  :  10.1016/j.bbadis.2021.166209

来源: Elsevier

【 摘 要 】

Tauopathies, including Alzheimer's disease (AD), are manifested by the deposition of well-characterized amyloid aggregates of Tau protein in the brain. However, it is rather unlikely that these aggregates constitute the major form of Tau responsible for neurodegenerative changes. Currently, it is postulated that the intermediates termed as soluble oligomers, assembled on the amyloidogenic pathway, are the most neurotoxic form of Tau. However, Tau oligomers reported so far represent a population of poorly characterized, heterogeneous and unstable assemblies. In this study, to obtain the oligomers, we employed the aggregation-prone K18 fragment of Tau protein with deletion of Lys280 (K18.280) linked to a hereditary tauopathy. We have described a new procedure of inducing aggregation of mutated K18 which leads either to the formation of nontoxic amyloid fibrils or neurotoxic globular oligomers, depending on its phosphorylation status. We demonstrate that PKAphosphorylated K18.280 oligomers are toxic to hippocampal neurons, which is manifested by loss of dendritic spines and neurites, and impairment of cell-membrane integrity leading to cell death. We also show that N1, the soluble N-terminal fragment of prion protein (PrP), protects neurons from the oligomers-induced cytotoxicity. Our findings support the hypothesis on the neurotoxicity of Tau oligomers and neuroprotective role of PrP-derived fragments in AD and other tauopathies. These observations could be useful in the development of therapeutic strategies for these diseases.

【 授权许可】

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