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Prion-Like Propagation of Post-Translationally Modified Tau in Alzheimer’s Disease: A Hypothesis

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Abstract

The microtubule-associated protein Tau plays a key role in the neuropathology of Alzheimer’s disease by forming intracellular neurofibrillary tangles. Tau in the normal physiological condition helps stabilize microtubules and transport. Tau aggregates due to various gene mutations, intracellular insults and abnormal post-translational modifications, phosphorylation being the most important one. Other modifications which alter the function of Tau protein are glycation, nitration, acetylation, methylation, oxidation, etc. In addition to forming intracellular aggregates, Tau pathology might spread in a prion-like manner as revealed by several in vitro and in vivo studies. The possible mechanism of Tau spread can be via bulk endocytosis of misfolded Tau species. The recent studies elucidating this mechanism have mainly focussed on the aggregation and spread of repeat domain of Tau in the cell culture models. Further studies are needed to elucidate the prion-like propagation property of full-length Tau and its aggregates in a more intense manner in vitro as well as in vivo conditions. Varied post-translational modifications can have discrete effects on aggregation propensity of Tau as well as its propagation. Here, we review the prion-like properties of Tau and hypothesize the role of glycation in prion-like properties of Tau. This post-translationally modified Tau might have an enhanced propagation property due to differential properties conferred by the modifications.

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Abbreviations

AD:

Alzheimer’s Disease

AMPA:

a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

PTMs:

Post-translational modifications

AGEs:

Advanced Glycation End products

PHFs:

Paired helical filaments

CML:

Carboxymethyl lysine

LRP:

Laminin receptor precursor

LRP1:

LDL receptor related protein 1

RAGEs:

Receptor for Advanced Glycation End products

CNS:

Central nervous system

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Acknowledgements

Shweta Kishor Sonawane acknowledges a fellowship from the Department of Biotechnology (DBT), India. The authors acknowledge Abhishek Balmik and Nalini Vijay Gorantla for proofreading the manuscript and useful comments.

Funding

This project was supported in part by grants from the Department of Science and Technology—Science and Engineering Research Board (DST-SERB, Young Investigator grant): SB/YS/LS-355/2013, Department of Biotechnology from Neuroscience Task Force (Medical

Biotechnology-Human Development & Disease Biology (DBT-HDDB))-BT/PR/15780/MED/30/1629/2015 and in-house CSIR-National Chemical Laboratory grant MLP029526 and CSIR-network project BSC0115.

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  1. Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India

    Shweta Kishor Sonawane & Subashchandrabose Chinnathambi

  2. Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India

    Shweta Kishor Sonawane & Subashchandrabose Chinnathambi

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Sonawane, S.K., Chinnathambi, S. Prion-Like Propagation of Post-Translationally Modified Tau in Alzheimer’s Disease: A Hypothesis. J Mol Neurosci 65, 480–490 (2018). https://doi.org/10.1007/s12031-018-1111-5

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