Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 187, Issue 6, Pages 1222-1229Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2017.01.019
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Funding
- NlH/National Institute on Aging [R01 AG044372]
- NIH/National Institute of Neurological Diseases and Stroke grant [R01 NS082730]
- Jean P. Schultz Biomedical Research Endowment
- Secchia Family Foundation Research Fund
- BrightFocus Foundation grant [A2013364S]
- Department of Veterans Affairs, NH/National Institute of Neurological Diseases and Stroke grant [1U01NS086659-01]
- National Institute of Aging Boston University Alzheimer's Disease Center grant [P30AG13846, 0572063345-5]
- Northwestern Alzheimer's Disease Center grant [AG13854]
- NADC Neuropathology Core Tissue Bank
- Michigan Alzheimer's Disease Center grant [P30AG053760]
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Pathological changes to the tau protein, including conformational changes and aggregation, are major hallmarks of a group of neurodegenerative disorders known as tauopathies. Among the conformational changes are alterations involving the extreme amino terminus of the protein, known as the phosphatase-activating domain (PAD). Aberrant PAD exposure induces a signaling cascade that leads to disruption of axonal transport, a critical function for neuronal survival. Conformational display of PAD is an early marker of pathological tau in Alzheimer disease (AD), but its role in other tauopathies has yet to be firmly established. We used a relatively novel N-terminal, conformation-sensitive antibody, TNT2, to determine whether misfolding in the amino terminus (ie, PAD exposure) occurs in non-AD tauopathies. We found that TNT2 specifically labeled pathological tau in post-mortem human brain tissue from Pick disease, progressive supranuclear palsy, corticobasal degeneration, and chronic traumatic encephalopathy, but did not Label nonpathological, parenchymal tau. Tau13, another N-terminal antibody, was not sensitive to pathological N-terminal conformations. Tau13 did not readily distinguish between normal (ie, parenchymal tau) and pathological tau species and showed a range of effectiveness at identifying tau pathologies in the non-AD tauopathies. These findings demonstrate that the conformational display of the PAD in tau represents a common pathological event in many tauopathies.
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