Peer-reviewedCC BYCell
Physiological brain clearance architecture revealed by neuronal protein tracing
10 affiliations
- 1Gladstone Institute of Neurological Disease, San Francisco, CA, USA
- 2Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
- 3Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA
- 4Institute for Intelligent Biotechnologies, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
- 5Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- 6Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- 7Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA
- 8Institute for Intelligent Biotechnologies, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- 9Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- 10Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: [email protected]
Abstract
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.
Related
- The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features
- Mitotic centromeres organize in repeat-subunits with specialized histone landscape and multi-domain architecture as revealed by expansion microscopy
- Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development
- Molecular mechanism of drought resistance in oat roots revealed using integrated physiological and multi-omics analyses.
- Bridging innate and adaptive immunity: A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance
BibTeX
@article{chayama2026physiological,
title = {{Physiological brain clearance architecture revealed by neuronal protein tracing}},
author = {Yuichi Chayama and Nalini R. Rao and Daniela Perla and Zimo Zhang and Madigan M. Reid and Sophia Nelson and Xinlan Wen and Bella Ding and Jessica R. Blumenfeld and Amanda Apolonio and Sahith Doddipalli and Haoyue Zhou and Sena Gül Turhan and Pu-Yun Shih and Matthias Brendel and Ying‐Hui Fu and Ali Ertürk and Zeynep Ilgin Kolabas and Yadong Huang and Andrew C. Yang},
journal = {Cell},
year = {2026},
month = may,
doi = {10.1016/j.cell.2026.04.048},
url = {https://doi.org/10.1016/j.cell.2026.04.048},
note = {CC BY},
}
RIS
TY - JOUR
TI - Physiological brain clearance architecture revealed by neuronal protein tracing
AU - Yuichi Chayama
AU - Nalini R. Rao
AU - Daniela Perla
AU - Zimo Zhang
AU - Madigan M. Reid
AU - Sophia Nelson
AU - Xinlan Wen
AU - Bella Ding
AU - Jessica R. Blumenfeld
AU - Amanda Apolonio
AU - Sahith Doddipalli
AU - Haoyue Zhou
AU - Sena Gül Turhan
AU - Pu-Yun Shih
AU - Matthias Brendel
AU - Ying‐Hui Fu
AU - Ali Ertürk
AU - Zeynep Ilgin Kolabas
AU - Yadong Huang
AU - Andrew C. Yang
PY - 2026
DA - 2026/05/29
JO - Cell
DO - 10.1016/j.cell.2026.04.048
UR - https://doi.org/10.1016/j.cell.2026.04.048
AB - 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.
SN - 0092-8674
SN - 1097-4172
ER -