Earliest Stages of Tau Conformational Changes are Related to the Appearance of a Sequence of Specific Phospho-Dependent Tau Epitopes in Alzheimer's Disease1
Abstract
Neurofibrillary tangles (NFT) and dystrophic neurites represent dense cytoplasmic accumulations of abnormal polymers in the brain of patients with Alzheimer's disease (AD). These polymers are referred to as paired helical filaments (PHFs) whose main structural core is composed of tau protein. Tau processing has been associated with hyperphosphorylation and truncation that results in PHF assembly. Both molecular events appear to cause conformational change of tau molecules [11,17,32]. In this regard, in a previous work focused on the analysis of patterns of immunolabeling in pre-tangle cells, we found that regional changes precede the structural modifications in tau [32]. In the present study, we further analyzed the early stages of tau processing in pre-tangle cells by using a variety of immunological markers of specific N-terminus phosphorylation tau sites. We used AT100, TG-3, AT8, pT231, Alz-50, Tau-C3 and 423 antibodies that recognize different abnormal tau epitopes in AD brains. These antibodies were combined and analyzed using a confocal microscope. Our results indicate that the early stages of abnormal tau processing are characterized by a sequential appearance of specific phospho-dependent epitope. The cascade of appearance of the antibodies is: pT231 --> TG-3 --> AT8 -->AT100 --> Alz-50. In addition; truncation at Asp-421 of the C-terminus of tau protein, as detected by Tau-C3, is also an early molecular event in tau protein aggregation prior to PHF formation in AD.
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S199 and T231 are two of the earliest phosphorylated sites on tau in Alzheimer's disease.
“S199 and T231 are two of the earliest phosphorylated sites on tau in AD (Maurage et al., 2003, Luna-Munoz et al., 2007), and tau phosphorylated at S396 is found in paired helical filaments (Bramblett et al., 1993).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Luna-Munoz et al., 2007
Tau phosphorylated at Thr231 is detected in the pre-tangle stage in AD brains.
“similar to tau phosphorylated at Ser262/356, tau phosphorylated at Thr231 is detected in the pre-tangle stage in AD brains [89]”
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Self-citationDendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice
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- Authors
- Luna-Muñoz, J., Chávez-Macías, L., García-Sierra, F., & Mena, R.
- Affiliations
- Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, México, D.F. México
- Hospital General de México (MX)
- Department of Physiology, Cell Biology CINVESTAV-IPN, México, D.F. México
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (MX)
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2007-12-25
- Volume
- 12
- Issue
- 4
- Pages
- 365-375
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1744236062
- Cited by
- 233
- References
- 5
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 21 · 2023: 17 · 2022: 16 · 2021: 17 · 2020: 20 · 2019: 14 · 2018: 12 · 2017: 3 · 2016: 12 · 2015: 11 · 2014: 17 · 2013: 15 · 2012: 10
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau hyperphosphorylation
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Antibodies, Epitopes, Brain, Humans, Immunohistochemistry, Middle Aged, Phosphorylation, Neurofibrillary Tangles, tau Proteins, Microscopy, Confocal, Plaque, Amyloid
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