Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage

Shafiei, Scott S.; Guerrero-Muñoz, Marcos J.; Castillo-Carranza, Diana L.

doi:10.3389/fnagi.2017.00083

Cited by 241 publications

(214 citation statements)

References 96 publications

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“…When tau becomes hyperphosphorylated, it forms intracellular NFTs predominantly in large pyramidal neurons of the entorhinal cortex, hippocampus, association cortex, and other cortical regions as the disease advances (4, 5). Although it is unclear whether the NFTs themselves, tau oligomers released prior to NFT formation, or perhaps both, lead to cell death (40), the endpoint of NFT accumulation is a classic hallmark seen on post-mortem examination of the brains of patients with AD. NFTs can be measured using routine detergent (sarkosyl) extractions, and sarkosyl-insoluble tau correlates with the pathological features of this altered protein that accumulates in vivo .…”

Section: Resultsmentioning

confidence: 99%

(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia

Voorhees

Remy

Cintrón-Pérez

et al. 2018

Biological Psychiatry

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Section: Resultsmentioning

confidence: 99%

(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia

Voorhees

Remy

Cintrón-Pérez

et al. 2018

Biological Psychiatry

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“…It is not known how and why these diverse tau morphologies arise, or whether conversion from one tau morphology to another is possible. It is also noteworthy that some evidence implicates soluble aggregates of oligomeric tau as an additional, if not a primary, substrate for tau-mediated neurotoxicity (149–151). …”

Section: Tau Protein In Diseasementioning

confidence: 99%

Small-molecule PET Tracers for Imaging Proteinopathies

Mathis

Lopresti

Ikonomović

et al. 2017

Seminars in Nuclear Medicine

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In this chapter, we provide a review of the challenges and advances in developing successful positron emission tomography (PET) imaging agents for three major types of aggregated amyloid proteins – amyloid-beta (Aβ), tau, and alpha-synuclein (α-syn). These three amyloids are involved in the pathogenesis of a variety of neurodegenerative diseases, referred to as proteinopathies or proteopathies, that include Alzheimer’s disease, Lewy body dementias, multiple system atrophy, and frontal temporal dementias among others. In the Introduction, we briefly discuss the history of amyloid in neurodegenerative diseases and describe why progress in developing effective imaging agents has been hampered by the failure of crystallography to provide definitive ligand-protein interactions for rational radioligand design efforts. Instead, the field has relied on largely serendipitous, trial and error methods to achieve useful and specific PET amyloid imaging tracers for Aβ, tau, and α-syn deposits. Because many of the proteopathies involve more than one amyloid protein, it is important to develop selective PET tracers for the different amyloids to help assess the relative contribution of each to total amyloid burden. We utilize Pittsburgh Compound B (PiB) to illustrate some of the critical steps in developing a potent and selective Aβ PET imaging agent. Other selective Aβ and tau PET imaging compounds have followed similar pathways in their developmental processes. Success for selective α-syn PET imaging agents has not been realized yet, but work is ongoing in multiple laboratories throughout the world. In the tau sections, we provide background regarding 3-repeat (3R) and 4-repeat (4R) tau proteins and how they can affect the binding of tau radioligands in different tauopathies. We review the ongoing efforts to assess the properties of tau ligands, which are useful in 3R, 4R or combined 3R/4R tauopathies. Finally, we describe in the α-syn sections recent attempts to develop selective tracers to image α-synucleinopathies.

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“…Dephosphorylated tau is very stable extracellularly,a nd the affinity of dephosphorylated tau to bind the M1 and M3 muscarinic receptors is nearly tenfold higher than that of acetylcholine;m oreover,u nlike acetylcholine, dephosphorylated tau does not induce desensitisationu pon repeated stimulation. [53,54] Through the aforementioned characteristics, dephosphorylated tau induces an increase in intracellular calcium, which leads to cellular toxicitya sw ell as possible additional hyperphosphorylation and misfolding of tau [53][54][55] (Figure 1, number 13).…”

Section: Perisynaptic Toxicityoftaumentioning

confidence: 99%

Transcellular Spreading of Tau in Tauopathies

2018

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Tau, a microtubule-associated protein playing a key role in a group of neurodegenerative diseases such as Alzheimer's disease, spreads throughout the brain, inducing pathology. A model akin to the spreading of prions has been raised owing to similar characteristics of inducing an abnormal protein conformation as a method of self-amplification, spreading protein aggregates over anatomically linked pathways. The search to identify the "seeds" that induce conformational change has received much attention; however, less is known about the mechanisms by which tau is transmitted from cell to cell, so-called "transcellular spreading". In this review, we gather evidence regarding the spreading of tau throughout the brain and provide an overview of methods by which tau can be released from neurons as well as taken up. Furthermore, we bring together mechanisms of neurotoxicity behind tau spreading. Advancing our understanding about the spreading of tau can guide the search for therapeutic options for multiple neurodegenerative diseases aggregating tau.

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Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage

Cited by 241 publications

References 96 publications

(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia

(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia

Small-molecule PET Tracers for Imaging Proteinopathies

Transcellular Spreading of Tau in Tauopathies

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