Cellular factors modulating the mechanism of tau protein aggregation

Fontaine, Sarah N.; Sabbagh, Jonathan J.; Baker, Jeremy D.; Martinez-Licha, Carlos R.; Darling, April L.; Dickey, Chad A.

doi:10.1007/s00018-015-1839-9

Cited by 51 publications

(57 citation statements)

References 249 publications

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“…Previous studies reported that Tau is phosphorylated at the aforementioned sites by phospho‐kinases such as GSK3β, mitogen‐activated protein kinase (MAPK), and cyclin‐dependent kinase (CDK)5 (Fontaine et al ., 2015). Thus, we tested the increase in the concentration of these kinases in our experimental model 3 h after injection of monomers and oligomers of Aβ1‐42 in hTau mice.…”

Section: Resultsmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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Section: Resultsmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…There are several detailed reviews that cover structure, function, and post-translational modification of the tau protein (Fontaine et al , 2015; Lee and Leugers, 2012; Morris et al , 2011). Tau is encoded for by the MAPT gene found on chromosome 17, a gene that is mutated in several tauopathies including FTD (Ferrari et al , 2011) and PSP (Im et al , 2015).…”

Section: The Tau Protein – Functions and Dysfunctionsmentioning

confidence: 99%

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

Kulbe

Hall

2017

Progress in Neurobiology

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In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, football, football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression.

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“…Some of the cellular structures and proteins for which interaction of the respective domains has been suggested are designated by the arrows shown below. This scheme summarizes informations from several excellent reviews, from which more detailed descriptions of the different modifications and their effect on tau in addition to those mentioned in the text can be obtained: [8,9,10,11,12]. (B) Different oligomerization states of tau are shown.…”

Section: Tau Hyperphosphorylation and Its Relation To Admentioning

confidence: 99%

“…In addition to phosphorylation, tau is also subject to a number of other covalent modifications, such as ubiquitination, sumoylation, acetylation, and glycosylation, all affecting its biological activities [49,50] reviewed in [10].…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

“…Oxidative stress, caused by mitochondrial dysfunction as discussed in the next chapter, will also lead to malfunction of the ubiquitin/proteasome system and thus affect tau toxicity [59]. Although the exact regulatory relationships still need to be elucidated, Nglycosylation seems to enhance tau aggregation, while OGlcNAcetylation has the opposite effect (reviewed in [10,60]). …”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

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Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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Cellular factors modulating the mechanism of tau protein aggregation

Cited by 51 publications

References 249 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

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