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Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models

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Abstract

The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance; however, it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediate the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to Alzheimer disease and cerebral amyloid angiopathy.

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Acknowledgments

We wish to express our gratitude to Dr. K. V. Kuchibhotla, Dr. A. Serrano-Pozo and Dr. T. L. Spires-Jones for fruitful discussions and careful reading and editing of the manuscript. This work was supported by the National Institute of Health (Grant No. EB000768).

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Authors and Affiliations

  1. Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA

    Michal Arbel-Ornath, Eloise Hudry, Steven Hou, Julia L. Gregory, Lingzhi Zhao, Matthew P. Frosch, Steven M. Greenberg & Brian J. Bacskai

  2. Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 149, 13th St., Charlestown, MA, 02129, USA

    Katharina Eikermann-Haerter

  3. Department of Biostatistics, Harvard School of Public Health, 50 Staniford Street, Boston, MA, USA

    Rebecca A. Betensky

  4. C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 114, 16th St., Charlestown, MA, 02129, USA

    Matthew P. Frosch

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  1. Michal Arbel-Ornath
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  2. Eloise Hudry
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  3. Katharina Eikermann-Haerter
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  7. Rebecca A. Betensky
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  8. Matthew P. Frosch
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  10. Brian J. Bacskai
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Correspondence to Brian J. Bacskai.

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Arbel-Ornath, M., Hudry, E., Eikermann-Haerter, K. et al. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models. Acta Neuropathol 126, 353–364 (2013). https://doi.org/10.1007/s00401-013-1145-2

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