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Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain.

Day RJ, Mason MJ, Thomas C, Poon WW, Rohn TT - PLoS ONE (2015)

Bottom Line: Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin.In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3.Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Science Building, Room 228, Boise State University, Boise, Idaho, 83725, United States of America.

ABSTRACT
Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

No MeSH data available.


Related in: MedlinePlus

Identification of TauC3-labeled structures as apparent corpora amylacea in VaD.(A): Bright-field staining utilizing the TauC3 antibody in the dentate gyrus of a representative VaD showing the presence of numerous round labeled structures that were ring-like in appearance (inset). (B): Representative bright-field staining utilizing HT7, an anti-body to full-length Tau did not label these round structures although numerous neurons were labeled. (C): Representative labeling of the TauC3 in an aged-matched control case indicating a relative paucity of labeling. Scale bars in Panels A-C represent 50 μm. (D): Quantitative analysis of the number of round structures in the hippocampi indicated a significant difference between VaD cases (n = 7, ±S.D.) and aged-matched controls (n = 4, ±S.D.), *p = .008. (E-G): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and the nuclear stain, DAPI (blue) indicated that the round circular structures labeled by TauC3 are not nuclei (merge, G). (H-J): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and TUNEL to label apoptotic cells (green) indicated that the round circular structures labeled by TauC3 are not apoptotic cells by in large (merge, J). Scale bars in Panels E-J represent 10 μm.
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pone.0132637.g002: Identification of TauC3-labeled structures as apparent corpora amylacea in VaD.(A): Bright-field staining utilizing the TauC3 antibody in the dentate gyrus of a representative VaD showing the presence of numerous round labeled structures that were ring-like in appearance (inset). (B): Representative bright-field staining utilizing HT7, an anti-body to full-length Tau did not label these round structures although numerous neurons were labeled. (C): Representative labeling of the TauC3 in an aged-matched control case indicating a relative paucity of labeling. Scale bars in Panels A-C represent 50 μm. (D): Quantitative analysis of the number of round structures in the hippocampi indicated a significant difference between VaD cases (n = 7, ±S.D.) and aged-matched controls (n = 4, ±S.D.), *p = .008. (E-G): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and the nuclear stain, DAPI (blue) indicated that the round circular structures labeled by TauC3 are not nuclei (merge, G). (H-J): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and TUNEL to label apoptotic cells (green) indicated that the round circular structures labeled by TauC3 are not apoptotic cells by in large (merge, J). Scale bars in Panels E-J represent 10 μm.

Mentions: Bright-field staining utilizing the TauC3 antibody consistently labeled the presence of numerous round structures that were ring-like in appearance in the dentate gyrus (Fig 2A). To determine if labeling within these structures was specific to caspase-cleaved tau, similar experiments were performed utilizing the anti-tau antibody HT7. Although this antibody labeled numerous neurons in the dentate gyrus region of VaD cases, there was a complete lack of staining within these round structures (Fig 2B). In addition, in age-matched control cases, these structures were only infrequently observed following application of the TauC3 antibody (Fig 2C). Quantitative analysis of these structures in the hippocampus revealed a statistically significant difference in the number of these structures between VaD and age matched controls (Fig 2D). In an attempt to identify these structures, immunofluorescence double labeling was undertaken. Initially double labeling was performed with the TauC3 antibody and the nuclear stain DAPI. Co-localization was not observed (Fig 2E–2G), providing evidence that the spherical structures were not nuclei. To determine if labeled TauC3 structures were apoptotic cells, double labeling was assessed together with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). As indicated in Fig 2H–2J, co-localization was not observed providing evidence that these found structures are not apoptotic structures. Based on the morphological appearance of these spherical, translucent structures, we hypothesize they represent corpora amylacea (CA).


Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain.

Day RJ, Mason MJ, Thomas C, Poon WW, Rohn TT - PLoS ONE (2015)

Identification of TauC3-labeled structures as apparent corpora amylacea in VaD.(A): Bright-field staining utilizing the TauC3 antibody in the dentate gyrus of a representative VaD showing the presence of numerous round labeled structures that were ring-like in appearance (inset). (B): Representative bright-field staining utilizing HT7, an anti-body to full-length Tau did not label these round structures although numerous neurons were labeled. (C): Representative labeling of the TauC3 in an aged-matched control case indicating a relative paucity of labeling. Scale bars in Panels A-C represent 50 μm. (D): Quantitative analysis of the number of round structures in the hippocampi indicated a significant difference between VaD cases (n = 7, ±S.D.) and aged-matched controls (n = 4, ±S.D.), *p = .008. (E-G): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and the nuclear stain, DAPI (blue) indicated that the round circular structures labeled by TauC3 are not nuclei (merge, G). (H-J): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and TUNEL to label apoptotic cells (green) indicated that the round circular structures labeled by TauC3 are not apoptotic cells by in large (merge, J). Scale bars in Panels E-J represent 10 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4498690&req=5

pone.0132637.g002: Identification of TauC3-labeled structures as apparent corpora amylacea in VaD.(A): Bright-field staining utilizing the TauC3 antibody in the dentate gyrus of a representative VaD showing the presence of numerous round labeled structures that were ring-like in appearance (inset). (B): Representative bright-field staining utilizing HT7, an anti-body to full-length Tau did not label these round structures although numerous neurons were labeled. (C): Representative labeling of the TauC3 in an aged-matched control case indicating a relative paucity of labeling. Scale bars in Panels A-C represent 50 μm. (D): Quantitative analysis of the number of round structures in the hippocampi indicated a significant difference between VaD cases (n = 7, ±S.D.) and aged-matched controls (n = 4, ±S.D.), *p = .008. (E-G): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and the nuclear stain, DAPI (blue) indicated that the round circular structures labeled by TauC3 are not nuclei (merge, G). (H-J): Immunofluorescence double labeling in a representative VaD case utilizing TauC3 (red) and TUNEL to label apoptotic cells (green) indicated that the round circular structures labeled by TauC3 are not apoptotic cells by in large (merge, J). Scale bars in Panels E-J represent 10 μm.
Mentions: Bright-field staining utilizing the TauC3 antibody consistently labeled the presence of numerous round structures that were ring-like in appearance in the dentate gyrus (Fig 2A). To determine if labeling within these structures was specific to caspase-cleaved tau, similar experiments were performed utilizing the anti-tau antibody HT7. Although this antibody labeled numerous neurons in the dentate gyrus region of VaD cases, there was a complete lack of staining within these round structures (Fig 2B). In addition, in age-matched control cases, these structures were only infrequently observed following application of the TauC3 antibody (Fig 2C). Quantitative analysis of these structures in the hippocampus revealed a statistically significant difference in the number of these structures between VaD and age matched controls (Fig 2D). In an attempt to identify these structures, immunofluorescence double labeling was undertaken. Initially double labeling was performed with the TauC3 antibody and the nuclear stain DAPI. Co-localization was not observed (Fig 2E–2G), providing evidence that the spherical structures were not nuclei. To determine if labeled TauC3 structures were apoptotic cells, double labeling was assessed together with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). As indicated in Fig 2H–2J, co-localization was not observed providing evidence that these found structures are not apoptotic structures. Based on the morphological appearance of these spherical, translucent structures, we hypothesize they represent corpora amylacea (CA).

Bottom Line: Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin.In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3.Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Science Building, Room 228, Boise State University, Boise, Idaho, 83725, United States of America.

ABSTRACT
Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

No MeSH data available.


Related in: MedlinePlus