Recent studies of atomic-resolution structures of tau protein and structure-based inhibitors

Abstract

Background: Alzheimer’s disease (AD) is one of the most popular tauopathies. Neurofibrillary tangles and senile plaques are widely recognized as the pathological hallmarks of AD, which are mainly composed of tau and β-amyloid (Aβ) respectively. Recent failures of drugs targeting Aβ have led scientists to scrutinize the crucial impact of tau in neurodegenerative diseases. Mutated or abnormal phosphorylated tau protein loses affinity with microtubules and assembles into pathological accumulations. The aggregation process closely correlates to two amyloidogenic core of PHF6 (³⁰⁶VQIVYK³¹¹) and PHF6* (²⁷⁵VQIINK²⁸⁰) fragments. Moreover, tau accumulations display diverse morphological characteristics in different diseases, which increases the difficulty of providing a unifying neuropathological criterion for early diagnosis.

Results: This review mainly summarizes atomic-resolution structures of tau protein in the monomeric, oligomeric and fibrillar states, as well as the promising inhibitors designed to prevent tau aggregation or disaggregate tau accumulations, recently revealed by experimental and computational studies. We also systematically sort tau functions, their relationship with tau structures and the potential pathological processes of tau protein.

Conclusion: The current progress on tau structures at atomic level of detail expands our understanding of tau aggregation and related pathology. We discuss the difficulties in determining the source of neurotoxicity and screening effective inhibitors. We hope this review will inspire new clues for designing medicines against tau aggregation and shed light on AD diagnosis and therapies.

Key words： tau; paired helical filaments; inhibitor; cryo-electron microscopy; molecular dynamics simulation

ACKNOWLEDGEMENTS

We thank Prof. Guanghong Wei for helpful discussion. This work was supported by the National Natural Science Foundation of China (Nos. 11704256 and 11932013).

COMPLIANCE WITH ETHICS GUIDELINES

The authors Lili Zhu and Zhenyu Qian declare that they have no conflict of interest or financial conflicts to disclose.

OPEN ACCESS

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