====== Tau pathology ======


[[Tau]] [[pathology]] refers to the accumulation and abnormal aggregation of tau protein in the brain, which is a hallmark of several neurodegenerative disorders, collectively known as **tauopathies**. The most well-known of these diseases is **[[Alzheimer’s disease]] (AD)**, but tau pathology is also a key feature of other conditions such as:

- **Progressive Supranuclear Palsy (PSP)**
- **Corticobasal Degeneration (CBD)**
- **Frontotemporal Dementia with Tau (FTD-Tau)**
- **Chronic Traumatic Encephalopathy (CTE)**
- **Pick’s Disease**

### **Tau Protein and Its Function**
Tau is a **microtubule-associated protein (MAP)** primarily found in neurons. Its normal function includes:
- Stabilizing **microtubules** (which help maintain neuronal structure and facilitate transport).
- Regulating **axonal transport** by interacting with motor proteins.
- Participating in signaling pathways.

Tau is normally **soluble** and highly **phosphorylated** under physiological conditions, but its phosphorylation is tightly regulated.

### **Pathological Tau Aggregation**
In tauopathies, tau undergoes **hyperphosphorylation**, causing it to:
1. **Dissociate from microtubules**, leading to destabilization and neuronal dysfunction.
2. **Misfold and aggregate**, forming insoluble filaments and neurofibrillary tangles (NFTs).
3. **Spread** in a prion-like manner across interconnected brain regions.

### **Mechanisms of Tau Pathology**
- **Hyperphosphorylation**: Increased phosphorylation reduces tau’s affinity for microtubules, leading to its accumulation in the cytoplasm.
- **Truncation and cleavage**: Proteolytic enzymes can break tau into toxic fragments.
- **Misfolding and aggregation**: Tau misfolds into β-sheet structures, forming paired helical filaments (PHFs) and NFTs.
- **Spreading**: Pathological tau can propagate between neurons, contributing to disease progression.

### **Tau Pathology in Alzheimer’s Disease**
- **Neurofibrillary tangles (NFTs)** correlate with cognitive decline.
- Tau pathology starts in the **entorhinal cortex** and spreads to the **hippocampus** and **neocortex**.
- **Stages of tau pathology (Braak Staging)**:
  - **Stages I-II**: Confined to the transentorhinal region.
  - **Stages III-IV**: Involves the limbic system and hippocampus.
  - **Stages V-VI**: Spreads to the neocortex, leading to widespread neurodegeneration.

### **Diagnosis of Tau Pathology**
- **Biomarkers**:
  - CSF tau (total tau, phosphorylated tau).
  - PET imaging using tau tracers (e.g., Flortaucipir, MK-6240).
- **Postmortem histopathology**:
  - Immunohistochemistry for phosphorylated tau.
  - Silver staining techniques.

### **Therapeutic Approaches**
1. **Tau-targeting immunotherapy**: Monoclonal antibodies to clear extracellular tau (e.g., semorinemab, gosuranemab).
2. **Tau phosphorylation inhibitors**: Kinase inhibitors targeting GSK-3β, CDK5.
3. **Microtubule stabilizers**: Epothilone D, Davunetide.
4. **Gene therapy and antisense oligonucleotides (ASOs)**: Targeting tau expression at the RNA level.