Drieu A, Du S, Storck SE, Rustenhoven J, Papadopoulos Z, Dykstra T, Zhong F, Kim K, Blackburn S, Mamuladze T, Harari O, Karch CM, Bateman RJ, Perrin R, Farlow M, Chhatwal J, Dominantly Inherited Alzheimer Network, Hu S, Randolph GJ, Smirnov I, Kipnis J. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature. 2022 Nov;611(7936):585-593. Epub 2022 Nov 9 PubMed.

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  1. One of the major roles of the CSF is waste clearance, which, as stated by the authors, becomes inefficient with aging.

    This paper unravels a novel regulator of CSF flow—border macrophages that phagocytose extracellular matrix around arteries to allow proper pulsation of CSF through the brain parenchyma. By using very creative tools, the authors deplete this population, or manipulate their function, to gain more insight into underlying mechanisms.

    I think that this is a truly novel and exciting new frontier in the study of debris clearance in aging-related diseases. As opposed to many of the current approaches that focus on enhancing clearance of specific aggregates (such as anti-amyloid antibodies), improving CSF flow by targeting macrophages could affect overall clearance of debris, and therefore could be a much more robust approach for neurodegenerative diseases.

    View all comments by Tal Iram

  2. This is another hallmark study by the Kipnis group. Here, they demonstrate a role for parenchymal border macrophages in the regulation of CSF flow along blood vessels in the brain, commonly referred to as para- (or peri-)vascular transport of CSF. Indeed, they show that a particular set of macrophages samples CSF content on its way in and out of the brain. They report that reduced macrophage function was accompanied with reduced CSF, or tracer, transport. The function of the macrophages further affected arterial motion, and the authors presented evidence for their role in Aβ clearance.

    These results are intriguing for several reasons, not least linking immunological cells with CSF transport, brain-clearance processes, and mechanisms behind altered arterial motion in aging and in the abnormal accumulation of substances such as Aβ. Further, these cells can be therapeutic targets to modify CSF transport, and thereby, parenchymal clearance. The findings also have implications for our understanding of impaired CSF transport during aging, and of Aβ accumulation in Alzheimer’s disease.

    From my perspective, these novel findings may have great impact.

    View all comments by Per Kristian Eide

  3. This study, along with some other recent studies, indicates that perivascular space stromal components, which have been poorly investigated, are much more heterogeneous and dynamic than was once recognized. Exploring this heterogeneity and the physiology of these spaces is critical, because research in this area may inform on novel treatment targets and disease predispositions.

    View all comments by Rupal Mehta

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  1. Perivascular Macrophages: New Target in Aging and Alzheimer’s Disease?