Tau Spreading Network Mapping via Spatial Transcriptomics in PSP
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experiment670 wordssynced 2026-04-02
Hypothesis
Primary Hypothesis: 4R-tau pathology in PSP originates in specific vulnerability hotspots (subcortical nuclei, brainstem) and spreads trans-synaptically along anatomically connected neural networks, following prion-like templating mechanisms.
Secondary Hypothesis: The pattern of tau spreading correlates with clinical phenotypes (Richardson's syndrome vs. variants) and can be predicted by connectome architecture derived from structural/functional MRI.
Pathway / Mechanism Diagram
graph TD
A["Tau Misfolding in Donor Neuron"] --> B["Tau Oligomer Formation"]
B --> C["Secretion via Exosomes"]
B --> D["Direct Synaptic Transfer"]
B --> E["Tunneling Nanotubes"]
C --> F["Extracellular Tau Uptake"]
D --> F
E --> F
F --> G["Templated Misfolding in Recipient"]
G --> H["Prion-like Propagation"]
H --> I["Braak Stage Progression"]
I --> J["Entorhinal Cortex (Stage I-II)"]
J --> K["Hippocampus (Stage III-IV)"]
K --> L["Neocortex (Stage V-VI)"]
G --> M["Microglial Activation"]
M --> N["Neuroinflammation"]
N --> O["Accelerated Tau Spread"]
O --> H
style A fill:#5d4400,color:#e0e0e0
style L fill:#ef5350,color:#e0e0e0
style H fill:#006494,color:#e0e0e0
Open Question Source
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Hypothesis
Primary Hypothesis: 4R-tau pathology in PSP originates in specific vulnerability hotspots (subcortical nuclei, brainstem) and spreads trans-synaptically along anatomically connected neural networks, following prion-like templating mechanisms.
Secondary Hypothesis: The pattern of tau spreading correlates with clinical phenotypes (Richardson's syndrome vs. variants) and can be predicted by connectome architecture derived from structural/functional MRI.
Pathway / Mechanism Diagram
Mermaid diagram (expand to render)
Open Question Source
This experiment addresses the critical knowledge gap from the [Experiment Priority Index](/experiments/experiment-priority-index) (rank 6): "Tau spreading network mapping via spatial transcriptomics in human PSP brain" and the CBS/PSP Cure Roadmap question: "Where does tau start and how does it spread?"
Validation Protocol
Study Design
Type: Cross-sectional neuropathological study with spatial genomics