Misfolded Tau Templates Normal Tau
Pathological tau conformers seed conversion of native tau.
- Microtubule stabilizer: Native tau role (axonal transport protein)
- Hyperphosphorylation: Pathological trigger (detachment from microtubules)
- Neurofibrillary tangle: Aggregate hallmark (paired helical filaments)
- MAPT: Key gene (encodes tau protein)
Placeholder: templating mechanism overview
Placeholder text: misfolded tau seeds conformational conversion of monomers.
Placeholder highlight: seeded templating is prion-like, not spontaneous.
Placeholder: why aggregates accumulate
Placeholder text: clearance pathways are overwhelmed by tau aggregates.
Release From the Affected Neuron
Pathological tau exits the donor neuron into extracellular space.
- Exosomes, free tau: Release routes (and synaptic vesicles)
- Neuronal activity: Trigger (and cell stress)
- Oligomers, fragments: Species released (seeding-competent tau)
- CSF / PET tau tracers: Detection method (biomarker assays)
Placeholder: release mechanisms
Placeholder text: exosomal and free tau release routes described here.
Placeholder highlight: activity-dependent release links network use to spread.
Uptake By a Connected Neuron
Extracellular tau seeds are internalized by a neighboring neuron.
- Endocytosis: Uptake routes (receptor-mediated entry)
- LRP1: Candidate receptor (implicated tau receptor)
- Endosomal escape: Compartment (seed reaches cytosol)
- Restarts templating: Outcome (in new cell)
Placeholder: uptake mechanism
Placeholder text: receptor-mediated endocytosis of tau seeds explained here.
Placeholder highlight: uptake completes the cell-to-cell transfer cycle.
Spread Along Neural Network Connections
Tau pathology follows synaptic connectivity, not simple diffusion.
- Connectome-based: Spread axis (not physical proximity)
- PET tau tracking: Evidence (longitudinal human studies)
- Tauopathy mouse models: Model support (seeded spread along tracts)
- High-connectivity hubs: Hub vulnerability (preferentially affected)
Placeholder: connectivity-based propagation
Placeholder text: network topology determines tau spread pathways.
Placeholder highlight: denser networks accelerate propagation across regions.
Braak-Stage Anatomical Progression Pattern
Tau pathology advances entorhinal cortex to neocortex in stereotyped order.
- Braak NFT stages I–VI: Staging scheme (Braak & Braak, 1991)
- Transentorhinal cortex: Earliest site (clinically silent stage)
- ~Stage IV–V: Dementia threshold (limbic to neocortical)
- Primary neocortex: Latest site (advanced-stage involvement)
Placeholder: six Braak NFT stages
Placeholder text: entorhinal, limbic, and neocortical stage progression.
Placeholder highlight: staging correlates with cognitive decline severity.
Braak NFT stage → region → clinical correlate