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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

Confirmation of caspase-cleaved tau within corpora amylacea.(A): Representative bright field staining in a VaD hippocampal brain section utilizing PAS that specifically labels CA in brain tissue. Labeled CA (magenta color, arrows) were in the vicinity of neurons in the granule cell layer of the dentate gyrus that were counter-stained with hematoxylin. (B): Representative bright-field labeling of numerous CA in the hippocampus of a VaD case utilizing an anti-ubiquitin, a specific marker for CA. (C and D): Representative immunofluorescence double-labeling in a VaD case at high magnification (C) and low magnification (D) indicating the co-localization of ubiquitin (green) together with the TauC3 antibody (red) within CA. In Panel D, the nuclei were also stained with nuclear stain, DAPI. All scale bars are equivalent to 10 μm except for Panel D, which represents 50 μm.
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pone.0132637.g003: Confirmation of caspase-cleaved tau within corpora amylacea.(A): Representative bright field staining in a VaD hippocampal brain section utilizing PAS that specifically labels CA in brain tissue. Labeled CA (magenta color, arrows) were in the vicinity of neurons in the granule cell layer of the dentate gyrus that were counter-stained with hematoxylin. (B): Representative bright-field labeling of numerous CA in the hippocampus of a VaD case utilizing an anti-ubiquitin, a specific marker for CA. (C and D): Representative immunofluorescence double-labeling in a VaD case at high magnification (C) and low magnification (D) indicating the co-localization of ubiquitin (green) together with the TauC3 antibody (red) within CA. In Panel D, the nuclei were also stained with nuclear stain, DAPI. All scale bars are equivalent to 10 μm except for Panel D, which represents 50 μm.

Mentions: To confirm these TauC3-positive structures were CA, we stained sections with PAS, a well known specific marker for CA [29]. Labeling of CA with PAS was evident within the same region, the dentate gyrus as for what we observed with TauC3 (arrows, Fig 3A). Additional experiments were undertaken to assess whether these structures stained positive for ubiquitin, another known marker for CA [30]. Application of an anti-ubiquitin antibody revealed an identical staining pattern as compared to TauC3 (Fig 3B) and this same anti-ubiquitin antibody strongly co-localized with TauC3 following double-label immunofluorescence studies (Fig 3C and 3D). Taken together, Figs 2 and 3 supported the presence of truncated tau within CA of the human VaD brain.


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)

Confirmation of caspase-cleaved tau within corpora amylacea.(A): Representative bright field staining in a VaD hippocampal brain section utilizing PAS that specifically labels CA in brain tissue. Labeled CA (magenta color, arrows) were in the vicinity of neurons in the granule cell layer of the dentate gyrus that were counter-stained with hematoxylin. (B): Representative bright-field labeling of numerous CA in the hippocampus of a VaD case utilizing an anti-ubiquitin, a specific marker for CA. (C and D): Representative immunofluorescence double-labeling in a VaD case at high magnification (C) and low magnification (D) indicating the co-localization of ubiquitin (green) together with the TauC3 antibody (red) within CA. In Panel D, the nuclei were also stained with nuclear stain, DAPI. All scale bars are equivalent to 10 μm except for Panel D, which represents 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132637.g003: Confirmation of caspase-cleaved tau within corpora amylacea.(A): Representative bright field staining in a VaD hippocampal brain section utilizing PAS that specifically labels CA in brain tissue. Labeled CA (magenta color, arrows) were in the vicinity of neurons in the granule cell layer of the dentate gyrus that were counter-stained with hematoxylin. (B): Representative bright-field labeling of numerous CA in the hippocampus of a VaD case utilizing an anti-ubiquitin, a specific marker for CA. (C and D): Representative immunofluorescence double-labeling in a VaD case at high magnification (C) and low magnification (D) indicating the co-localization of ubiquitin (green) together with the TauC3 antibody (red) within CA. In Panel D, the nuclei were also stained with nuclear stain, DAPI. All scale bars are equivalent to 10 μm except for Panel D, which represents 50 μm.
Mentions: To confirm these TauC3-positive structures were CA, we stained sections with PAS, a well known specific marker for CA [29]. Labeling of CA with PAS was evident within the same region, the dentate gyrus as for what we observed with TauC3 (arrows, Fig 3A). Additional experiments were undertaken to assess whether these structures stained positive for ubiquitin, another known marker for CA [30]. Application of an anti-ubiquitin antibody revealed an identical staining pattern as compared to TauC3 (Fig 3B) and this same anti-ubiquitin antibody strongly co-localized with TauC3 following double-label immunofluorescence studies (Fig 3C and 3D). Taken together, Figs 2 and 3 supported the presence of truncated tau within CA of the human VaD brain.

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