Thiazin red as a neuropathological tool for the rapid diagnosis of Alzheimer’s disease in tissue imprints

Luna-Muñoz, José; Peralta-Ramirez, Janneth; Chávez-Macías, Laura; Harrington, Charles R.; Wischik, Claude M.; Mena, Raúl

doi:10.1007/s00401-008-0431-x

Cited by 40 publications

(35 citation statements)

References 35 publications

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“…The plaques were verified by highly specific immunostainings for Aβ using the 6E10 monoclonal antibody. These findings were also confirmed using Thiazine Red + which is a marker to differentiate the fibrillar state from the nonfibrillar state of Aβ in AD1516. The Aβ plaques were very prominent in all brain areas in 12-month-old mice.…”

Section: Discussionsupporting

confidence: 54%

“…Therefore, the Thiazine Red + staining is not specific for our mouse model, where we crossbred APP_SweDI with GFP_FLT1 mice. While Thiazine Red is an accurate marker to differentiate the fibrillar from the nonfibrillar state of Aβ in AD16 we cannot prove yet the exact binding site of Thiazine Red + in platelets. However it is known, that platelets contain high amounts of APP and produce small amounts of Aβ, predominantly Aβ 40 over Aβ 42 (ref 10) Thus it seems likely that Thiazine Red binds Aβ or APP in platelets.…”

Section: Discussionmentioning

confidence: 84%

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Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Kniewallner

Wenzel

Humpel

2016

Sci Rep

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Strong evidence shows an association between cerebral vascular diseases and Alzheimer´s disease (AD). In order to study the interaction of beta-amyloid (Aβ) plaques with brain vessels, we crossbred an AD mouse model (overexpressing amyloid precursor protein with the Swedish-Dutch-Iowa mutations, APP_SweDI) with mice expressing green fluorescent protein (GFP) under the flt-1/VEGFR1 promoter in vessels (GFP_FLT1). Our data show, that only very few Aβ plaques were seen in 4-months old mice, focused in the mammillary body and in the lateral septal nucleus. The number of plaques markedly increased with age being most prominent in 12-months old mice. Thiazine Red was used to verify the plaques. Several Thiazine Red+ inclusions were found in GFP+ vessels, but only in non-perfused 4-months old mice. These inclusions were verified by Resorufin stainings possibly representing cerebral amyloid angiopathy. The inclusions were also seen in non-crossbred APP_SweDI but not in wildtype and GFP_FLT1 mice. In order to characterize these inclusions Flow Cytometry (FACS) analysis demonstrated that platelets were specifically stained by Thiazine Red+, more pronounced when aggregated. In conclusion, our data show that Thiazine Red+ inclusions representing aggregated platelets are a first pathological sign in AD before plaque development and may become important therapeutic targets in early AD.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 84%

Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Kniewallner

Wenzel

Humpel

2016

Sci Rep

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“…However, in the last decade, various molecular probes have been developed for detection of amyloid fibrils (Table 1). In many cases, various derivatives or related structures of both CR and ThT have been shown to be useful for in vitro and ex vivo monitoring of amyloid fibrils [63][64][65][66][67][68]. In addition, development of noninvasive methods to quantitate amyloid deposits is of great use in the diagnosis of amyloid diseases.…”

Section: Overview Of Molecular Probes For Amyloid Fibril Detectionmentioning

confidence: 98%

Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status

2009

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Because understanding amyloid fibrillation in molecular detail is essential for development of strategies to control amyloid formation and overcome neurodegenerative disorders, increased understanding of present molecular probes as well as development of new probes are of utmost importance. To date, the binding modes of these molecular probes to amyloid fibrils are by no means adequately described or understood, and the large number of studies on Thioflavin T (ThT) and Congo Red (CR) binding have resulted in models that are incomplete and conflicting. Different types of binding sites are likely to be present in amyloid fibrils with differences in binding modes. ThT may bind in channels running parallel to the long axis of the fibril. In the channels, ThT may bind in either a monomeric or dimeric form of which the molecular conformation is likely to be planar. CR may bind in grooves formed along the β-sheets as a planar molecule in either a monomeric or supramolecular form.

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“…TR is a fluorescent dye that recognizes ␤-pleated sheet conformation in the neurofibrillary pathology of AD (61). We used the criteria of TR staining to differentiate between neurons containing seemingly more mature NFTs and those containing granular diffuse aggregates of Tau characteristic of early pretangle neurons.…”

Section: Tau Dimers Associate To Form Oligomers But Not Long Filamementioning

confidence: 99%

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

Patterson

Remmers

et al. 2011

Journal of Biological Chemistry

295

340

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Neurofibrillary tangles, composed of insoluble aggregates of the microtubule-associated protein Tau, are a pathological hallmark of Alzheimer disease (AD) and other tauopathies. However, recent evidence indicates that neuronal dysfunction precedes the formation of these insoluble fibrillar deposits, suggesting that earlier prefibrillar Tau aggregates may be neurotoxic. To determine the composition of these aggregates, we have employed a photochemical cross-linking technique to examine intermolecular interactions of full-length Tau in vitro. Using this method, we demonstrate that dimerization is an early event in the Tau aggregation process and that these dimers selfassociate to form larger oligomeric aggregates. Moreover, using these stabilized Tau aggregates as immunogens, we generated a monoclonal antibody that selectively recognizes Tau dimers and higher order oligomeric aggregates but shows little reactivity to Tau filaments in vitro. Immunostaining indicates that these dimers/oligomers are markedly elevated in AD, appearing in early pathological inclusions such as neuropil threads and pretangle neurons as well as colocalizing with other early markers of Tau pathogenesis. Taken as a whole, the work presented herein demonstrates the existence of alternative Tau aggregates that precede formation of fibrillar Tau pathologies and raises the possibility that these hierarchical oligomeric forms of Tau may contribute to neurodegeneration.

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Thiazin red as a neuropathological tool for the rapid diagnosis of Alzheimer’s disease in tissue imprints

Cited by 40 publications

References 35 publications

Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Thiazine Red+ platelet inclusions in Cerebral Blood Vessels are first signs in an Alzheimer’s Disease mouse model

Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status

Characterization of Prefibrillar Tau Oligomers in Vitro and in Alzheimer Disease

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