🧪
hypothesis

Tau propagation through muscarinic receptor-mediated BBB transcytosis

Hypothesis

Tau propagation through muscarinic receptor-mediated BBB transcytosis

The hypothesis proposes that pathological tau enters or spreads through the CNS via M1/M3 muscarinic receptor-mediated BBB transcytosis, with LRP1 and other uptake pathways contributing.
🧬 CHRM1; CHRM3; LRP1🩺 neurodegeneration🎯 Composite 40%💱 $0.47▲15.7%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 3 oppose
✓ All Quality Gates Passed
Mechanistic 0.38 (15%) Evidence 0.34 (15%) Novelty 0.74 (12%) Feasibility 0.30 (12%) Impact 0.32 (12%) Druggability 0.28 (10%) Safety 0.24 (8%) Competition 0.68 (6%) Data Avail. 0.40 (5%) Reproducible 0.30 (5%) KG Connect 0.50 (8%) 0.400 composite
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Composite40%

🧪 Overview

The hypothesis proposes that pathological tau enters or spreads through the CNS via M1/M3 muscarinic receptor-mediated BBB transcytosis, with LRP1 and other uptake pathways contributing. This is the least development-ready program because LRP1-mediated tau uptake is credible but the muscarinic BBB mechanism remains speculative and experimentally under-tested.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix3 supports3 contradicts
Supports
LRP1 mediates neuronal tau uptake and trans-synaptic spread.
PMID:29847938
Supports
Peripheral tau is detectable in Alzheimer's disease and correlates with CNS pathology measures.
PMID:26159303
Supports
Muscarinic receptors can regulate tau secretion in cellular models.
PMID:32084339
Contradicts
LRP1 and neuronal-network propagation are more established explanations than M1/M3-mediated BBB transcytosis.
PMID:32296178
Contradicts
The proposed intracerebral tau-seeding experiment would not directly test peripheral-to-CNS BBB transcytosis.
PMID:NA
Contradicts
CHRM1/CHRM3 perturbation would create major cognitive, autonomic, vascular, and BBB confounds.
PMID:NA
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — CHRM1;

No curated PDB or AlphaFold mapping for CHRM1; yet. Search RCSB →

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for CHRM1; CHRM3; LRP1 →

No DepMap CRISPR Chronos data found for CHRM1; CHRM3; LRP1.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

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💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

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