Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid

Area of Science:

• Neuroimmunology
• Cerebrospinal Fluid Dynamics
• Macrophage Biology

Background:

• Macrophages are crucial for tissue homeostasis.
• Perivascular and leptomeningeal macrophages, termed parenchymal border macrophages (PBMs), are strategically located near the central nervous system (CNS) but their functions are understudied.
• PBMs interact closely with cerebrospinal fluid (CSF).

Purpose of the Study:

• To investigate the role of PBMs in CNS physiology and cerebrospinal fluid (CSF) dynamics.
• To identify specific PBM subpopulations involved in regulating CSF flow.
• To explore the implications of PBM dysfunction in aging and Alzheimer's disease (AD).

Main Methods:

• Identification of LYVE1+ PBM subpopulation associated with the brain arterial tree.
• Pharmacological and genetic depletion of PBMs to assess CSF flow.
• Macrophage colony-stimulating factor (MCSF) administration to restore PBM function.
• Single-nucleus RNA sequencing in human patients with Alzheimer's disease (AD) and a mouse model of AD.

Main Results:

• PBMs, particularly LYVE1+ macrophages, regulate arterial motion essential for CSF flow dynamics.
• PBM depletion leads to extracellular matrix accumulation, impaired CNS perfusion, and reduced clearance.
• Age-related PBM dysfunction and impaired CSF dynamics were reversible with MCSF treatment.
• Alzheimer's disease (AD) patients and mouse models show altered PBM pathways including phagocytosis, endocytosis, and interferon-γ signaling.

Conclusions:

• Parenchymal border macrophages (PBMs) are identified as novel regulators of CSF flow dynamics.
• Targeting PBMs offers a potential therapeutic strategy for brain clearance deficits in aging and Alzheimer's disease (AD).
• Understanding PBM function is critical for maintaining CNS homeostasis and treating neurodegenerative conditions.