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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 189, 4737-4755.e17 (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; Cerebrospinal-fluid Absorption; Central-nervous-system; Glymphatic System; Choroid-plexus; Subarachnoid Space; Interstitial Fluid; Lymphatic Vessels; Drainage Pathways; Nasal Lymphatics; Mouse Model
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 189, Issue: 15, Pages: 4737-4755.e17 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute for Intelligent Biotechnologies (IBIO)
Grants National Institutes of Health
National Institute of Neurological Disorders and Stroke
Alzheimer's Association
Burroughs Wellcome Fund Career Awards at the Scientific Interface
Ludwig Family Foundation
Longevity Impetus Grant from Norn Group
UCSF Sandler Program for Breakthrough Biomedical Research New Frontier Research Award
Dolby Family
Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within Munich Cluster for Systems Neurology