The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer′s Disease (AD)

Mroczko, Barbara; Groblewska, Magdalena; Litman‐Zawadzka, Ala

doi:10.3390/ijms20194661

Cited by 55 publications

(39 citation statements)

References 168 publications

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“…Tau proteins have important biological functions; their microtubule stabilizing role has been studied for a long time. A correct tau isoform ratio is necessary for maintaining brain cell homeostasis and preventing neurodegenerative diseases [141]. The repeat regions (together with short joining sequences) are the microtubule binding domain of tau.…”

Section: Tau Isoforms Domain Structure Post-translational Modificatmentioning

confidence: 99%

“…Free sulfhydryl groups in tau increase the predisposition for polymerization of the monomer. This is a multistep chemical process that shows different stages as reviewed in [141] (Table 3). According to the newest hypothesis, diffusible TauOs are toxic, but larger polymers probably are non-toxic assemblies [174].…”

Section: The Structure Of Tau Oligomers and Fibrilsmentioning

confidence: 99%

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Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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Section: Tau Isoforms Domain Structure Post-translational Modificatmentioning

confidence: 99%

Section: The Structure Of Tau Oligomers and Fibrilsmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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“…Phosphorylation of tau at specific epitopes is widely appreciated to contribute to AD (6, 8), with acetylation of tau at specific sites also shown to contribute to the evolution of tau pathology (18, 19). While it has now become evident that the insoluble accumulations of tau in the AD are likely not the primary toxic species (5–7, 69), the specific mechanisms by which monomers or soluble oligomers of tau with AD-relevant PTMs cause neuronal dysfunction have not been full delineated. This is due in part to the fact that the majority of studies have used models in which tau is overexpressed, which can result in outcomes that may not be directly relevant to AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…While it is clear that tau is central to AD pathogenesis, the concept of large insoluble NFTs in AD and other tauopathies being the principle mediators of neuronal toxicity has been gradually abandoned (5). Instead, toxicity appears to result from soluble or oligomeric forms of tau that exhibit increased, disease-associated phosphorylation and acetylation at specific residues altering its turnover and function (6, 7).…”

Section: Introductionmentioning

confidence: 99%

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Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

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21 Background: A defining pathological hallmark of the progressive neurodegenerative 22 disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal 23 post-translational modifications (PTMs). These include phosphorylation at Threonine 231 24 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is 25 recognized to play a central role in pathogenesis of AD, the precise mechanisms by which 26 these abnormal PTMs contribute to the neural toxicity of tau is unclear.27Methods: Human 0N4R tau (wild type) was expressed in touch receptor neurons of the 28 genetic model organism C. elegans through single-copy gene insertion. Defined 29 mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 30 genome editing. These mutations included T231E and T231A, to mimic phosphorylation 31 and phospho-ablation of a commonly observed pathological epitope, respectively, and 32 K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response 33 assays were used to assess behavioral defects in the transgenic strains as a function of 34 age, and genetically-encoded fluorescent biosensors were used to measure the 35 morphological dynamics and turnover of touch neuron mitochondria. 36Results: Unlike existing tau overexpression models, C. elegans single-copy expression 37 of tau did not elicit overt pathological phenotypes at baseline. However, strains 38 expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited 39 reduced touch sensation and morphological abnormalities that increased with age. In 40 addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to 41 mitochondrial stress. 42 Conclusions: Limiting the expression of tau results in a genetic model where 43 pathological modifications and age result in evolving phenotypes, which may more closely 44 resemble the normal progression of AD. The finding that disease-associated PTMs 45 suppress compensatory responses to mitochondrial stress provides a new perspective 46 into the pathogenic mechanisms underlying AD. 47 modifications 49 BACKGROUND 50Alzheimer's disease (AD) is the most common degenerative brain disease in the aged 51 population. It is characterized by the progressive decline of cognition and memory, as 52 well as changes in behavior and personality (1). One of the key pathological hallmarks of 53 AD is neurofibrillary tangles (NFTs), which are primarily composed of abnormally modified 54 tau (2). Tau isolated from AD brain exhibits a number of posttranslational modifications 55 (PTMs); including increases in phosphorylation and acetylation at specific residues (3, 4). 56While it is clear that tau is central to AD pathogenesis, the concept of large insoluble NFTs 57 in AD and other tauopathies being the principle mediators of neuronal toxicity has been 58 gradually abandoned (5). Instead, toxicity appears to result from soluble or oligomeric 59 forms of tau that exhibit increased, disease-associated phosphorylation and acetylat...

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Synaptic Oligomers and Glial Cells in Alzheimer Disease

Grinberg

2023

JAMA Neurol

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The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer′s Disease (AD)

Cited by 55 publications

References 168 publications

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Synaptic Oligomers and Glial Cells in Alzheimer Disease

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