| p-tau231 — Phosphorylated Tau at Threonine 231 |
|---|
| Gene | [MAPT](/genes/mapt) |
| UniProt ID | P10636 |
| Phosphorylation Site | Threonine 231 (T231) |
| Molecular Weight | 45-65 kDa (isoform-dependent) |
| Subcellular Localization | Axons, microtubule-associated |
| Protein Family | Microtubule-associated protein (MAP) family |
| kinases | [GSK-3β](/entities/gsk3-beta), [CDK5](/proteins/cdk5), MARK |
Phosphorylated Tau at Threonine 231 (p-tau231) is a hyperphosphorylated form of the Tau protein encoded by the MAPT gene. Phosphorylation at T231 represents an early and critical event in tau pathogenesis, making p-tau231 one of the most sensitive biomarkers for Alzheimer's disease and other tauopathies.
The T231 phosphorylation site is particularly important because:
- Early Marker: Phosphorylation occurs early in AD progression, even before clinical symptoms
- Conformational Change: T231 phosphorylation promotes tau dimerization and oligomerization
- Microtubule Disruption: Severely impairs tau's ability to stabilize microtubules
- Aggregation Nucleation: Serves as a seed for neurofibrillary tangle formation
T231 is located in the:
- Proline-rich domain (PRR): Residues 151-244
- Adjacent to microtubule-binding repeats (R1-R4)
- Critical hinge region between N-terminal and C-terminal domains
Multiple kinases phosphorylate T231:
| Kinase |
Role |
Notes |
| GSK-3β |
Primary |
Hyperactive in AD brain |
| CDK5 |
Major |
Phosphorylates T231 efficiently |
| MARK/PAR-1 |
Early event |
Involved in tau spreading |
- PP2A: Major phosphatase dephosphorylating T231
- PP1: Minor contribution
- Activity reduced in AD brain
-
Microtubule Destabilization
- Reduced tau-microtubule binding
- Impaired axonal transport
- Synaptic dysfunction
-
Tau Aggregation
- p-tau231 promotes paired helical filament formation
- Serves as template for further phosphorylation
- Spreads between connected neurons
-
Neuronal Dysfunction
- Loss of neurotrophic support
- Mitochondrial transport defects
- Calcium dysregulation
p-tau231 serves as a "seed" for prion-like propagation:
- Released from dying neurons
- Taken up by neighboring cells
- Templates further tau pathology
p-tau231 is an early and specific biomarker for AD:
| Feature |
p-tau231 |
p-tau181 |
p-tau217 |
| Detectable in preclinical AD |
++ |
+ |
+ |
| Specificity for AD vs. other dementias |
+++ |
++ |
+++ |
| Correlation with tau PET |
++ |
++ |
+++ |
| Cerebrospinal fluid |
Available |
Available |
Available |
| Blood-based detection |
Emerging |
Available |
Emerging |
- Early Diagnosis: Detectable before clinical symptoms
- Disease Progression: Correlates with cognitive decline
- Treatment Monitoring: Potential biomarker for drug trials
- ELISA: Highly sensitive CSF detection
- SIMOA: Ultra-sensitive blood detection
- Western Blot: Semi-quantitative analysis
- Mass Spectrometry: Site-specific quantification
- Single molecule array (Simoa): Picoliter-scale detection
- Immuno-PCR: Enhanced sensitivity
- Blood p-tau231: Under development
- Kinase Inhibitors: GSK-3β, CDK5 modulators
- Phosphatase Activators: PP2A activators
- Anti-tau Antibodies: Immunotherapy targeting phosphorylated tau
- Aggregation Inhibitors: Prevent p-tau231 oligomerization
- Blood-based p-tau231 detection
- PET ligands for p-tau231
- Understanding kinase-phosphatase balance
- Clinical validation studies