4.8 Article

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-31257-9

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资金

  1. National Institute of Neurological Disorders and Stroke [NINDS K08NS089830]
  2. National Institute on Aging [R01NS100366, RF1AG057575]
  3. US Army Research Office [MURI W911NF1910280]
  4. Fondation Leducq Transatlantic Networks of Excellence Program
  5. Adelson Foundation
  6. EU Horizon 2020 research and innovation programme [666881]
  7. National Institute of Neurological Disorders and Stroke

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The study reveals that the pia mater, previously thought to confine fluid flow around blood vessels in the brain, is actually perforated and permissive to cerebrospinal fluid (CSF) flow. The pial structure and function are found to be associated with CSF transport and amyloid clearance, suggesting a previously unrecognized role of pia in regulating aging and disease in the brain.
Perivascular spaces (PVS) drain brain waste metabolites, but their specific flow paths are debated. Meningeal pia mater reportedly forms the outermost boundary that confines flow around blood vessels. Yet, we show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. The degree of pial coverage correlates with macrophage density and phagocytosis of CSF tracer. In vivo imaging confirms transpial influx of CSF tracer, suggesting a role of pia in CSF filtration, but not flow restriction. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced beta-amyloid deposits in PVS of old mice. We show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease. The precise boundaries and flow compartments of perivascular spaces in the brain are incompletely understood. Here the authors show that pia is perforated and permissive to CSF flow, forming three types of perivascular spaces that remodel with age, with an abnormal type arising in Alzheimer's disease and correlating with beta-amyloid burden and differential macrophage uptake.

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