TY - JOUR
T1 - Altered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis
AU - Ben-Nejma, Inés R.H.
AU - Keliris, Aneta J.
AU - Vanreusel, Verdi
AU - Ponsaerts, Peter
AU - Van der Linden, Annemie
AU - Keliris, Georgios A.
N1 - Score=10
Funding Information:
This study was supported by the Fund for Scientific Research Flanders (FWO) (grant agreements G067515N to AVdL and G048917N to GAK). The 9.4 T Bruker MR system was in part funded by the Flemish Impulse funding for heavy scientific equipment (42/FA010100/123 to AVdL).
Funding Information:
The authors thank Prof. Dr. Joanna L. Jankowsky (Baylor College of Medicine, Houston, TX, USA) and Prof. Dr. JoAnne McLaurin (Sunnybrook Health Sciences Centre, Toronto, Canada) for providing single transgenic tTA and APP male mice. We also express our gratitude to Dr. Jelle Praet for initial help in establishing and managing mouse colonies. We are indebted to Jasmijn Daans for help in performing immunostaining experiments. We thank other members of the Bio-Imaging lab, Johan Van Auderkerke for technical support and Prof. Marleen Verhoye for initial technical suggestions and discussion during meetings. The computational resources and services used in this work were provided by the HPC core facility CalcUA of the Universiteit Antwerpen, the VSC (Flemish Supercomputer Center), funded by the Hercules Foundation and the Flemish Government–department EWI.
Funding Information:
The authors thank Prof. Dr. Joanna L. Jankowsky (Baylor College of Medicine, Houston, TX, USA) and Prof. Dr. JoAnne McLaurin (Sunnybrook Health Sciences Centre, Toronto, Canada) for providing single transgenic tTA and APP male mice. We also express our gratitude to Dr. Jelle Praet for initial help in establishing and managing mouse colonies. We are indebted to Jasmijn Daans for help in performing immunostaining experiments. We thank other members of the Bio-Imaging lab, Johan Van Auderkerke for technical support and Prof. Marleen Verhoye for initial technical suggestions and discussion during meetings. The computational resources and services used in this work were provided by the HPC core facility CalcUA of the Universiteit Antwerpen, the VSC (Flemish Supercomputer Center), funded by the Hercules Foundation and the Flemish Government–department EWI.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Background: Alzheimer’s disease (AD) is an incurable neurodegenerative disorder characterised by the progressive buildup of toxic amyloid-beta (Aβ) and tau protein aggregates eventually leading to cognitive decline. Recent lines of evidence suggest that an impairment of the glymphatic system (GS), a brain waste clearance pathway, plays a key role in the pathology of AD. Moreover, a relationship between GS function and neuronal network integrity has been strongly implicated. Here, we sought to assess the efficacy of the GS in a transgenic Tet-Off APP mouse model of amyloidosis, in which the expression of mutant APP was delayed until maturity, mimicking features of late-onset AD—the most common form of dementia in humans. Methods: To evaluate GS function, we used dynamic contrast-enhanced MRI (DCE-MRI) in 14-month-old Tet-Off APP (AD) mice and aged-matched littermate controls. Brain-wide transport of the Gd-DOTA contrast agent was monitored over time after cisterna magna injection. Region-of-interest analysis and computational modelling were used to assess GS dynamics while characterisation of brain tissue abnormalities at the microscale was performed ex vivo by immunohistochemistry. Results: We observed reduced rostral glymphatic flow and higher accumulation of the contrast agent in areas proximal to the injection side in the AD group. Clustering and subsequent computational modelling of voxel time courses revealed significantly lower influx time constants in AD relative to the controls. Ex vivo evaluation showed abundant amyloid plaque burden in the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain-fluid circulation. Conclusions: In a context resembling late-onset AD in humans, we demonstrate the disruption of glymphatic function and particularly a reduction in brain-fluid influx in the AD group. We conjecture that the hindered circulation of cerebrospinal fluid is potentially caused by wide-spread astrogliosis and amyloid-related obstruction of the normal routes of glymphatic flow resulting in redirection towards caudal regions. In sum, our study highlights the translational potential of alternative approaches, such as targeting brain-fluid circulation as potential therapeutic strategies for AD.
AB - Background: Alzheimer’s disease (AD) is an incurable neurodegenerative disorder characterised by the progressive buildup of toxic amyloid-beta (Aβ) and tau protein aggregates eventually leading to cognitive decline. Recent lines of evidence suggest that an impairment of the glymphatic system (GS), a brain waste clearance pathway, plays a key role in the pathology of AD. Moreover, a relationship between GS function and neuronal network integrity has been strongly implicated. Here, we sought to assess the efficacy of the GS in a transgenic Tet-Off APP mouse model of amyloidosis, in which the expression of mutant APP was delayed until maturity, mimicking features of late-onset AD—the most common form of dementia in humans. Methods: To evaluate GS function, we used dynamic contrast-enhanced MRI (DCE-MRI) in 14-month-old Tet-Off APP (AD) mice and aged-matched littermate controls. Brain-wide transport of the Gd-DOTA contrast agent was monitored over time after cisterna magna injection. Region-of-interest analysis and computational modelling were used to assess GS dynamics while characterisation of brain tissue abnormalities at the microscale was performed ex vivo by immunohistochemistry. Results: We observed reduced rostral glymphatic flow and higher accumulation of the contrast agent in areas proximal to the injection side in the AD group. Clustering and subsequent computational modelling of voxel time courses revealed significantly lower influx time constants in AD relative to the controls. Ex vivo evaluation showed abundant amyloid plaque burden in the AD group coinciding with extensive astrogliosis and microgliosis. The neuroinflammatory responses were also found in plaque-devoid regions, potentially impacting brain-fluid circulation. Conclusions: In a context resembling late-onset AD in humans, we demonstrate the disruption of glymphatic function and particularly a reduction in brain-fluid influx in the AD group. We conjecture that the hindered circulation of cerebrospinal fluid is potentially caused by wide-spread astrogliosis and amyloid-related obstruction of the normal routes of glymphatic flow resulting in redirection towards caudal regions. In sum, our study highlights the translational potential of alternative approaches, such as targeting brain-fluid circulation as potential therapeutic strategies for AD.
KW - Glymphatic system
KW - Brain-fluid circulation
KW - Mature-onset tet-off mice
KW - Forebrain amyloidosis
KW - Amyloidbeta
KW - DCE-MRI
KW - Astrogliosis
KW - Inflammation
KW - Amyloid-beta
U2 - 10.1186/s13195-023-01175-z
DO - 10.1186/s13195-023-01175-z
M3 - Article
VL - 15
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 23
ER -