The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treat
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The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease Sanjib Guha 1
&
Gail V. W. Johnson 1 & Keith Nehrke 2
Received: 15 June 2020 / Accepted: 19 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Alzheimer’s disease . Tau phosphorylation . Neurodegeneration . Mitochondria . Therapeutic strategies
Introduction Alzheimer’s disease (AD) is the most common degenerative brain disease in the aged population. It is characterized by the progressive decline of cognition and memory, as well as changes in behavior and personality [1]. A defining pathological hallmark of the AD brain is the presence of insoluble neurofibrillary
* Sanjib Guha [email protected] Gail V. W. Johnson [email protected] Keith Nehrke [email protected] 1
Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
2
Department of Medicine, Nephrology Division, University of Rochester, Rochester 14642, NY, USA
tangles (NFTs), which are primarily composed of abnormally modified tau [2]. Tau isolated from AD brain tissues exhibits a number of posttranslational modifications (PTMs), with increases in phosphorylation being the most p
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