{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Gladstone Institute of Neurological Disease, San Francisco, CA, USA",
    "Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA",
    "Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA",
    "Institute for Intelligent Biotechnologies, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany",
    "Department of Neurology, University of California, San Francisco, San Francisco, CA, USA",
    "Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany",
    "Department 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",
    "Institute 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",
    "Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA",
    "Gladstone 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: andrew.yang@gladstone.ucsf.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yuichi Chayama"
    },
    {
      "affs": [
        0
      ],
      "name": "Nalini R. Rao",
      "orcid": "0000-0003-0913-5983"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniela Perla"
    },
    {
      "affs": [
        0
      ],
      "name": "Zimo Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Madigan M. Reid",
      "orcid": "0009-0002-0177-0691"
    },
    {
      "affs": [
        1
      ],
      "name": "Sophia Nelson"
    },
    {
      "affs": [
        0
      ],
      "name": "Xinlan Wen"
    },
    {
      "affs": [
        0
      ],
      "name": "Bella Ding"
    },
    {
      "affs": [
        2
      ],
      "name": "Jessica R. Blumenfeld",
      "orcid": "0000-0002-5470-6901"
    },
    {
      "affs": [
        0
      ],
      "name": "Amanda Apolonio"
    },
    {
      "affs": [
        0
      ],
      "name": "Sahith Doddipalli"
    },
    {
      "affs": [
        0
      ],
      "name": "Haoyue Zhou",
      "orcid": "0000-0001-5287-0030"
    },
    {
      "affs": [
        3
      ],
      "name": "Sena Gül Turhan"
    },
    {
      "affs": [
        4
      ],
      "name": "Pu-Yun Shih",
      "orcid": "0000-0002-9565-7958"
    },
    {
      "affs": [
        5
      ],
      "name": "Matthias Brendel",
      "orcid": "0000-0002-9247-2843"
    },
    {
      "affs": [
        6
      ],
      "name": "Ying‐Hui Fu",
      "orcid": "0000-0002-6628-0266"
    },
    {
      "name": "Ali Ertürk",
      "orcid": "0000-0001-5163-5100"
    },
    {
      "affs": [
        7
      ],
      "name": "Zeynep Ilgin Kolabas",
      "orcid": "0000-0002-0672-681X"
    },
    {
      "affs": [
        8
      ],
      "name": "Yadong Huang",
      "orcid": "0000-0002-5871-4589"
    },
    {
      "affs": [
        9
      ],
      "name": "Andrew C. Yang",
      "orcid": "0000-0002-6756-4746"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6kf1n94ym77y0.bib",
  "cited_by": 9,
  "doi": "10.1016/j.cell.2026.04.048",
  "fulltext_url": null,
  "id": "6kf1n94ym77y0",
  "issns": [
    "0092-8674",
    "1097-4172"
  ],
  "landing_url": "https://doi.org/10.1016/j.cell.2026.04.048",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Cerebrospinal fluid and hydrocephalus"
    ]
  ],
  "openalex": "W7162812019",
  "pdf_url": null,
  "pmcid": "PMC13225612",
  "pmid": "42214342",
  "published": "2026-05-29",
  "publisher": "Cell Press",
  "ris": "https://research.draconitic.com/paper/6kf1n94ym77y0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:53Z",
      "native_id": "W7162812019",
      "source": "openalex",
      "url": "https://doi.org/10.1016/j.cell.2026.04.048"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Cerebrospinal fluid and hydrocephalus",
      "subfield": "neuroscience"
    }
  ],
  "title": "Physiological brain clearance architecture revealed by neuronal protein tracing",
  "title_text": "Physiological brain clearance architecture revealed by neuronal protein tracing",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:36Z",
  "url": "https://research.draconitic.com/paper/6kf1n94ym77y0",
  "venue": "Cell",
  "versions": []
}