Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

Mosi Li, Akihiro Kitamura, Joshua Beverley, Juraj Koudelka, Jessica Duncombe, Ross Lennen, Maurits A. Jansen, Ian Marshall, Bettina Platt, Ulrich K. Wiegand, Roxana O. Carare, Rajesh N. Kalaria, Jeffrey J. Iliff, Karen Horsburgh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
3 Downloads (Pure)


Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-beta (A beta) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including A beta removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of A beta. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Original languageEnglish
Article number788519
Number of pages16
JournalFrontiers in Aging Neuroscience
Early online date13 Jan 2022
Publication statusPublished - 13 Jan 2022

Bibliographical note

Schematic diagrams in Figures 2, 8 are created

We gratefully acknowledge the grant support from the Alzheimer’s Society (152 (PG-157); 290 (AS-PG-15b-018); 228 (AS-DTC-2014-017), 314 (AS –PhD-16-006), and Alzheimer’s Research United Kingdom (ART-PG2010-3; ARUK-PG2013- 22; ARUK-PG2016B-6), and The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). ML and JB are funded by an Alzheimer’s Society Scotland Doctoral Training Programme and RS Macdonald Trust. ML was also funded by a China Scholarship Council (CSC)/University of Edinburgh scholarship.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author: (
The Supplementary Material for this article can be found online at: 2021.788519/full#supplementary- material


  • carotid stenosis
  • vascular pulsation
  • glymphatic function
  • vascular cognitive impairment
  • amyloid-beta (A beta)
  • cerebral amyloid angiopathy (CAA)


Dive into the research topics of 'Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment'. Together they form a unique fingerprint.

Cite this