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

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.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Guha S,Johnson GVW,Nehrke K

doi

10.1007/s12035-020-02084-0

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

5103-5120

issue

12

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-020-02084-0

journal_volume

57

pub_type

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