The tau phosphorylation pathway is central to Alzheimer's disease (AD) pathogenesis. Tau is a microtubule-associated protein that stabilizes neuronal microtubules. In AD, tau becomes hyperphosphorylated, leading to microtubule disassembly, tau aggregation into neurofibrillary tangles (NFTs), and neuronal death. The extent of neurofibrillary tangle pathology correlates strongly with cognitive decline in AD, making tau a critical therapeutic target.
¶ Gene and Protein Structure
The MAPT gene (Microtubule-Associated Protein Tau) located on chromosome 17q21.31 encodes tau protein. Tau has six isoforms ranging from 352 to 441 amino acids, generated by alternative splicing of exons 2, 3, and 10. The protein consists of:
- N-terminal projection domain: interacts with neuronal membranes and other tau molecules
- Proline-rich region: contains multiple phosphorylation sites
- Microtubule-binding domain: 3-4 repeat regions (R1-R4) that bind microtubules
- C-terminal tail: regulates tau aggregation
In the healthy brain, tau:
- Stabilizes microtubules in axons
- Facilitates axonal transport
- Regulates neuronal plasticity
- Modulates synaptic function
- Supports neurite outgrowth
flowchart TD
A[Tau Protein] --> B[Kinase Phosphorylation]
B --> C[Proline-Directed Kinases]
B --> D[Non-Proline-Directed Kinases]
C --> C1[GSK-3β]
C --> C2[CDK5]
C --> C3[JNK]
C --> C4[ERK1/2]
D --> D1[PKA]
D --> D2[CaMKII]
D --> D3[PKC]
D --> D4[TBK1]
E[Hyperphosphorylated Tau] --> F[Microtubule Disassembly]
E --> G[Tau Aggregation]
E --> H[NFT Formation]
GSK-3β (Glycogen Synthase Kinase-3β)
- Primary kinase responsible for tau hyperphosphorylation
- Phosphorylates tau at over 40 sites
- Activity increased in AD brain
- Inhibited by lithium, valproic acid, and Tideglusib
CDK5 (Cyclin-Dependent Kinase 5)
- Neuron-specific kinase activated by p35/p39
- Phosphorylates tau at multiple AD-relevant sites
- Dysregulated by calpain cleavage of p35 to p25
- Hyperactive in AD neurons
JNK (c-Jun N-terminal Kinase)
- Activated by cellular stress
- Phosphorylates tau at Ser46, Thr181
- Links oxidative stress to tau pathology
ERK1/2 (Extracellular Signal-Regulated Kinases)
- Mitogen-activated protein kinase pathway
- Phosphorylates tau at multiple sites
- Activated in early AD
PP2A (Protein Phosphatase 2A)
- Major tau phosphatase in brain
- Activity reduced in AD (~50%)
- PP2A inhibition promotes tau phosphorylation
- PP2A demethylation contributes to dysfunction
PP1 (Protein Phosphatase 1)
- Contributes to tau dephosphorylation
- Regulated by okadaic acid
- Activity compromised in AD
| Site |
Kinase |
Normal |
AD |
Functional Effect |
| Ser202 |
GSK-3β, CDK5 |
Low |
High |
Early marker |
| Thr205 |
GSK-3β, CDK5 |
Low |
High |
Microtubule binding loss |
| Ser212 |
GSK-3β |
Low |
High |
Aggregation enhancement |
| Ser214 |
GSK-3β |
Low |
High |
Phosphorylation-dependent |
| Thr231 |
GSK-3β, CDK5 |
Low |
High |
Conformation change |
| Ser262 |
CaMKII |
Low |
High |
Early microtubule loss |
| Ser396 |
GSK-3β |
Low |
High |
Late-stage marker |
| Ser404 |
GSK-3β, CDK5 |
Low |
High |
Aggregation enhancement |
- Normal brain: ~2-3 mol phosphate/mol tau
- AD brain: ~6-8 mol phosphate/mol tau
- Threshold for microtubule binding loss: ~3-4 mol phosphate/mol tau
Hyperphosphorylated tau undergoes:
- Conformational change exposing microtubule-binding domains
- Nucleation into small oligomers
- Formation of paired helical fragments (PHFs)
- Assembly into neurofibrillary tangles (NFTs)
- Tau oligomers: Most toxic species, transferable between neurons
- Paired helical filaments (PHFs): Insoluble, stable aggregates
- NFTs: End-stage intracellular inclusions
- Extracellular tau: Released, may propagate pathology
Tau pathology spreads through:
- Synaptic connections (prion-like)
- Tunneling nanotubes
- Extracellular vesicles
- Exosome release
| Stage |
Region Affected |
Clinical Correlation |
| I-II |
Transentorhinal cortex |
Preclinical |
| III-IV |
Limbic system (hippocampus) |
Mild cognitive impairment |
| V-VI |
Isocortex |
Moderate-severe dementia |
- Amyloid (Aβ) may initiate tau pathology spread
- Tau pathology correlates with cognitive decline
- Aβ+ tau+ = worse than either alone
- Tau PET predicts cognitive decline better than amyloid PET
- Lithium: GSK-3 inhibitor, repurposed for AD
- Tideglusib: Non-ATP competitive GSK-3 inhibitor
- Roscovitine: CDK5 inhibitor
- SP600125: JNK inhibitor
- PP2A activators: Sodium meta-arsenite
- Methylation restoration: Vitamin B12, folate
- Methylene blue derivatives: LMTM, TRx0237
- Natural compounds: Curcumin, epigallocatechin gallate
- Peptide-based inhibitors
- Active vaccination: AADvac1
- Passive antibodies: Gosuranemab, tilavonemab, semorinemab
- Anti-tau oligomer antibodies
- Mandelkow & Mandelkow, Tau in physiology and pathology (2011)
- Ballatore et al., Tau-mediated neurodegeneration (2007)
- Medina et al., GSK-3 and tau (2016)
- Baas & Black, Tau phosphorylation (1999)
- Avila et al., Tau phosphorylation in Alzheimer's disease (2014)
- Wang & Mandelkow, Tau in physiology and disease (2016)
- Furukawa et al., Tau aggregation inhibitors (2020)
- Hyman et al., National Institute on Aging criteria for AD (2012)