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Chayama, Y.* ; Rao, N.R.* ; Perla, D.* ; Zhang, Z.* ; Reid, M.* ; Nelson, S.* ; Wen, X.* ; Ding, B.* ; Blumenfeld, J.* ; Apolonio, A.* ; Doddipalli, S.* ; Zhou, H.* ; Turhan, S.G. ; Shih, P.Y.* ; Brendel, M.* ; Fu, Y.H.* ; Ertürk, A. ; Kolabas, Z.I. ; Huang, Y.* ; Yang, A.C.*

Physiological brain clearance architecture revealed by neuronal protein tracing.

Cell, DOI: 10.1016/j.cell.2026.04.048 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a “nearest exit” principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alzheimer’s Disease ; Brain Borders ; Brain Waste Clearance ; Cerebrospinal Fluid ; Cns Drainage ; Dura ; Immune Tolerance ; Neuroimmunology ; Skull
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Publisher Elsevier
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute for Intelligent Biotechnologies (IBIO)