TY - JOUR
T1 - Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid
AU - Dominantly Inherited Alzheimer Network
AU - Drieu, Antoine
AU - Du, Siling
AU - Storck, Steffen E.
AU - Rustenhoven, Justin
AU - Papadopoulos, Zachary
AU - Dykstra, Taitea
AU - Zhong, Fenghe
AU - Kim, Kyungdeok
AU - Blackburn, Susan
AU - Mamuladze, Tornike
AU - Harari, Oscar
AU - Karch, Celeste M.
AU - Bateman, Randall J.
AU - Perrin, Richard
AU - Farlow, Martin
AU - Chhatwal, Jasmeer
AU - Brosch, Jared
AU - Buck, Jill
AU - Farlow, Marty
AU - Ghetti, Bernardino
AU - Adams, Sarah
AU - Barthelemy, Nicolas
AU - Benzinger, Tammie
AU - Brandon, Susan
AU - Buckles, Virginia
AU - Cash, Lisa
AU - Chen, Charlie
AU - Chua, Jasmin
AU - Cruchaga, Carlos
AU - Denner, Darcy
AU - Dincer, Aylin
AU - Donahue, Tamara
AU - Fagan, Anne
AU - Feldman, Becca
AU - Flores, Shaney
AU - Franklin, Erin
AU - Joseph-Mathurin, Nelly
AU - Gonzalez, Alyssa
AU - Gordon, Brian
AU - Gray, Julia
AU - Gremminger, Emily
AU - Groves, Alex
AU - Hassenstab, Jason
AU - Hellm, Cortaiga
AU - Herries, Elizabeth
AU - Hoechst-Swisher, Laura
AU - Holtzman, David
AU - Hornbeck, Russ
AU - Graff-Radford, Neill
AU - Jack, Clifford
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/17
Y1 - 2022/11/17
N2 - Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, 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.
AB - Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85141714808&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05397-3
DO - 10.1038/s41586-022-05397-3
M3 - Article
C2 - 36352225
AN - SCOPUS:85141714808
SN - 0028-0836
VL - 611
SP - 585
EP - 593
JO - Nature
JF - Nature
IS - 7936
ER -