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Arc Institute
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The team engineered neurons to secrete an inert reporter (Syn-ZsG), tracing it from the brain outward without injecting to perturb the system. A bioorthogonal labeler that tags the neuronal proteome (Syn-PheRS) mapped the same way, ruling out a reporter artifact.
The brain works hard to clear waste, and impairments are central to neurodegeneration. In @cellcellpress.bsky.social, Innovation Investigator Andrew Yang and team map it from the inside out, following the brain's own proteins to see where waste actually goes.
While 'waste' is shorthand, thousands of proteins the brain sheds aren't inert junk; many likely signal to the immune system. Systematic study of brain clearance opens paths to rejuvenate it as an upstream target for neurodegeneration.
Access the paper: www.cell.com/cell/fulltex...
Disease disrupted clearance in two ways:
LPS-driven inflammation broke down the blood-brain barrier, shunting Syn-ZsG away from borders and into the blood.
In 5XFAD mice, amyloid pathology had the opposite effect, trapping proteins in the brain, with less reaching the brain borders.
Specific neuron types had spatially compartmentalized clearance: cortical neurons through dorsal dura; deep striatal neurons via skull base and nose. In this 'nearest exit' principle, a protein's origin dictates waste routing and immune cell encounters.
scRNA-seq showed skull-resident B cells dominate brain antigen sampling at this slow border. They upregulate MHC I and tolerogenic markers (PD-L1, Il10ra, Cd1d1), suggesting that the skull functions as an immune-tolerance niche for brain-derived proteins.
Investigating which exits are most important for the brain, pulse-chase showed that each border exit processes brain waste at different rates. Skull outflow was more than 20-fold is slower than the dura and nose.
Arc’s Virtual Cell Initiative focuses on the full-stack development of an accurate AI model to advance complex disease research. Executive Director Silvana Konermann joined TED’s Chris Anderson to talk about what we’re building.
www.ted.com/talks/silvan...
Neuronal proteins originating in the brain drained to the dura, skull, and nose, while injected CSF-tracer gathered in the neck’s lymph nodes. Like Schrödinger's cat, the act of injection itself may perturb the system being studied.
Arc Institute
Arc Institute
Silvana Konermann and the team at Arc Institute are trying to crack one of science's most difficult problems: why complex diseases like Alzheimer's and cancer remain so stubbornly unsolvable, even as ...
Neuronal protein tracing, unlike CSF tracers, reveals that brain clearance follows
a “nearest exit” principle through distinct border immune niches disrupted differently
by disease.
