Acute systemic LPS-exposure impairs perivascular CSF distribution in mice

Abstract

Background The exchange of cerebrospinal (CSF) and interstitial fluid is believed to be vital for waste clearance in the brain. The sleep-dependent glymphatic system, which is comprised of perivascular flow of CSF and is largely dependent on arterial pulsatility and astrocytic aquaporin-4 (AQP4) expression, facilitates much of this brain clearance. During the last decade, several observations have indicated that impaired glymphatic function goes hand in hand with neurodegenerative diseases. Since pathologies of the brain carry inflammatory components, we wanted to know how acute inflammation, e.g., with lipopolysaccharide (LPS) injections, would affect the glymphatic system. In this study, we aim to measure the effect of LPS on perivascular CSF distribution as a measure of glymphatic function. Methods Three hours after injection of LPS (1 mg/kg i.p.), C57bl/6 mice were (1) imaged for two CSF tracers, injected into cisterna magna, (2) transcardially perfused with buffer, or (3) used for physiological readouts. Tracer flow was imaged using a low magnification microscope on fixed brains, as well as using vibratome-cut slices for measuring tracer penetration in the brain. Cytokines, glial, and BBB-permeability markers were measured with ELISAs, Western blots, and immunohistochemistry. Cerebral blood flow was approximated using laser Doppler flowmetry, respiration and heart rate with a surgical monitor, and AQP4-polarization was quantified using confocal microscopy of immunolabeled brain sections. Results LPS-injections significantly lowered perivascular CSF tracer flow and penetration into the parenchyma. No differences in AQP4 polarization, cytokines, astroglial and BBB markers, cerebral blood flow, or respiration were detected in LPS-injected mice, although LPS did elevate cortical Iba1+ area and heart rate. Conclusions This study reports another physiological response after acute exposure to the bacterial endotoxin LPS, namely the statistically significant decrease in perivascular distribution of CSF. These observations may benefit our understanding of the role of systemic inflammation in brain clearance.

The Glymphatic System (En)during Inflammation

“…A recent study elucidated how the glymphatic system reacts to a peripheral inflammatory challenge [ 115 ]. In that study, there was reduced perivascular CSF flow as soon as three hours after peripheral LPS treatment at a single dose of 1 mg/kg in mice [ 115 ].…”

“…A recent study elucidated how the glymphatic system reacts to a peripheral inflammatory challenge [ 115 ]. In that study, there was reduced perivascular CSF flow as soon as three hours after peripheral LPS treatment at a single dose of 1 mg/kg in mice [ 115 ]. Other factors known to influence the glymphatic function were measured; respiration, cortical blood flow, astrogliosis, and AQP4 polarization were surprisingly unchanged at three hours, despite the reduction in CSF flow.…”

“…Other factors known to influence the glymphatic function were measured; respiration, cortical blood flow, astrogliosis, and AQP4 polarization were surprisingly unchanged at three hours, despite the reduction in CSF flow. The study points towards another physiological response of the glymphatic system after endotoxin exposure, as only the heart rate and the microglia activation were elevated in these mice [ 115 ]. In support of a model of suppressed glymphatic function after LPS injection, Erickson et al demonstrated reduced amyloid-β clearance 28 h after LPS exposure [ 116 ].…”

“…There is little doubt that glymphatic fluid transport is suppressed in acute and chronic neuroinflammatory conditions [ 27 , 37 , 70 , 115 ]. Depending on the nature of the inflammatory insult, stagnating fluid drainage will then contribute to edema formation, cytokine accumulation, and reactive responses of microglia, astrocytes, and/or neurons.…”

Dysfunction of the Glymphatic System as a Potential Mechanism of Perioperative Neurocognitive Disorders

“…Therefore, systemic inflammation influences the function of the glymphatic system based on the evidence that the structure and function of the glymphatic system are closely related to that of the BBB (Verheggen et al, 2018 ). Notably, a recent study found that lipopolysaccharide-induced systemic inflammation reduced perivascular CSF tracer flow and penetration into the parenchyma (Manouchehrian et al, 2021 ). These observations may be beneficial for our understanding of the role of systemic inflammation in glymphatic clearance.…”