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The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder. A defining hallmark of the AD brain is the presence of intraneuronal neurofibrillary tangles (NFTs) which are made up of abnormally modified tau, with aberrant phosphorylation being the most studied posttranslational modification (PTM). Although the accumulation of tau as NFTs is an invariant feature of the AD brain, it has become evident that these insoluble aggregates are likely not the primary pathogenic form of tau, rather soluble forms of tau with abnormal PTMs are the mediators of toxicity. The most prevalent PTM on tau is phosphorylation, with the abnormal modification of specific residues on tau playing a key role in its toxicity. Even though it is widely accepted that tau with aberrant PTMs facilitates neurodegeneration, the precise cellular mechanisms remain unknown. Nonetheless, there is an evolving conceptual framework that an important contributing factor may be selective pathological tau species compromising mitochondrial biology. Understanding the mechanisms by which tau with site-specific PTM impacts mitochondria is crucial for understanding the role tau plays in AD. Here, we provide a brief introduction to tau and its phosphorylation and function in a physiological context, followed by a discussion of the impact of soluble phosphorylated tau species on neuronal processes in general and mitochondria more specifically. We also discuss how therapeutic strategies that attenuate pathological tau species in combination with treatments that improve mitochondrial biology could be a potential therapeutic avenue to mitigate disease progression in AD and other tauopathies.

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Acknowledgments

We thank the members of the Mitochondrial Research and Interest Group at the University of Rochester Medical Center for their valuable suggestions and helpful discussions. The authors would like to acknowledge Bio-render for providing an online paid subscription platform (BioRender.com) to create all the figures.

Funding

This work was supported by NIH (R21AG060627 and R01AG067617) (GJ and KN).

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  1. Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA

    Sanjib Guha & Gail V. W. Johnson

  2. Department of Medicine, Nephrology Division, University of Rochester, Rochester, 14642, NY, USA

    Keith Nehrke

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  1. Sanjib Guha
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SG wrote the paper, made the figures, and reviewed all the cited articles. GJ and KN helped in writing the paper and critically revised the work. All authors read and approved the final manuscript.

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Guha, S., Johnson, G.V.W. & Nehrke, K. The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease. Mol Neurobiol 57, 5103–5120 (2020). https://doi.org/10.1007/s12035-020-02084-0

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