title: Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.
abstract: Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation.SIGNIFICANCE STATEMENTMicroinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.|Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
authors.forename: Minghuan
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642.|Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
authors.forename: SaiYue
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, iliffj@ohsu.edu Nedergaard@URMC.Rochester.edu.|Department of Anesthesiology and Perioperative Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon 97239, and.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
authors.affiliation: Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, iliffj@ohsu.edu Nedergaard@URMC.Rochester.edu.|Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Maiken
authors.identifier: 0000-0001-6502-6031
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism* / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000134:cerebrospinal fluid* / Q000473:pathology; D015398:Signal Transduction
keywords: glymphatic; microinfarct; vascular dementia