Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

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Journal Article

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National Institutes of Health/National Institute on Aging (AG034113, AG057496, AG078106)

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Macrophages are important players in the maintenance of tissue homeostasis. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1 + PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer’s disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.

Additional Information

Dominantly Inherited Alzheimer Network:

Richard Perrin, Celeste M. Karch, Randall J. Bateman, Jared Brosch, Jill Buck, Marty Farlow, Bernardino Ghetti, Jasmeer Chhatwal, Sarah Adams, Nicolas Barthelemy, Tammie Benzinger, Susan Brandon, Virginia Buckles, Lisa Cash, Charlie Chen, Jasmin Chua, Carlos Cruchaga, Darcy Denner, Aylin Dincer, Tamara Donahue, Anne Fagan, Becca Feldman, Shaney Flores, Erin Franklin, Nelly Joseph-Mathurin, Alyssa Gonzalez, Brian Gordon, Julia Gray, Emily Gremminger, Alex Groves, Jason Hassenstab, Cortaiga Hellm, Elizabeth Herries, Laura Hoechst-Swisher, David Holtzman, Russ Hornbeck, Gina Jerome, Sarah Keefe, Deb Koudelis, Yan Li, Jacob Marsh, Rita Martinez, Kwasi Mawuenyega, Austin McCullough, Eric McDade, John Morris, Joanne Norton, Kristine Shady, Wendy Sigurdson, Jennifer Smith, Peter Wang, Qing Wang, Chengjie Xiong, Jinbin Xu, Xiong Xu, Ricardo Allegri, Patricio Chrem Mendez, Noelia Egido, Aki Araki, Takeshi Ikeuchi, Kenji Ishii, Kensaku Kasuga, Jacob Bechara, William Brooks, Peter Schofield, Sarah Berman, Sarah Goldberg, Snezana Ikonomovic, William Klunk, Oscar Lopez, James Mountz, Neelesh Nadkarni, Riddhi Patira, Lori Smith, Beth Snitz, Sarah Thompson, Elise Weamer, Courtney Bodge, Stephen Salloway, Kathleen Carter, Duc Duong, Erik Johnson, Allan Levey, Lingyan Ping, Nicholas T. Seyfried, Colleen Fitzpatrick, Helena Chui, John Ringman, Gregory S. Day, Neill Graff-Radford, Morgan Graham, Sochenda Stephens, Chrismary De La Cruz, Jill Goldman, Arlene Mejia, Katie Neimeyer, James Noble, Anna Diffenbacher, Igor Yakushev, Johannes Levin, Jonathan Vöglein, Jane Douglas, Nick Fox, Miguel Grilo, Cath Mummery, Antoinette O’Connor, Bianca Esposito, Alison Goate, Alan Renton, Hisako Fujii, Michio Senda, Hiroyuki Shimada, Samantha Gardener (Edith Cowan University), Ralph Martins (Edith Cowan University), Hamid Sohrabi (Edith Cowan University), Kevin Taddei (Edith Cowan University), Susanne Gräber-Sultan, Lisa Häsler, Anna Hofmann, Mathias Jucker, Stephan Käser, Elke Kuder-Buletta, Christoph Laske, Oliver Preische, Christian Haass, Estrella Morenas-Rodriguez, Brigitte Nuscher, Ryoko Ihara, Akemi Nagamatsu, Yoshiki Niimi, Clifford Jack, Robert Koeppe, Neal Scott Mason, Colin Masters, Ulricke Obermüller



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