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):

1. Stages I-II: Confined to the transentorhinal region.
2. Stages III-IV: Involves the limbic system and hippocampus.
3. Stages V-VI: Spreads to the neocortex, leading to widespread neurodegeneration.

### Diagnosis of Tau Pathology - Biomarkers:

1. CSF tau (total tau, phosphorylated tau).
2. PET imaging using tau tracers (e.g., Flortaucipir, MK-6240).

- Postmortem histopathology:

1. Immunohistochemistry for phosphorylated tau.
2. 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.