Circadian Dysregulation of the Choroid Plexus with Age and Amyloid Pathology
Authors List
Deidre Jansson1,2,3, Ryan O’Boyle2,3, Mathew Sevao2,3, Taylor Pedersen2,3, Ron Vered2,3, Elizabeth Gino2,3, Molly Braun2,3, Samantha Keil2,3, Jeffrey Iliff2,3
1University of Auckland, Auckland, New Zealand, 2University of Washington, Seattle, USA,
3VA Puget Sound Health Care System, Seattle, USA
The choroid plexus (CP) is a highly vascularized stromal tissue located in each of the four brain ventricles. Encased by ciliated epithelial cells, the CP is responsible for the majority of cerebrospinal fluid (CSF) production in the brain. The CP also delivers trophic factors to surrounding brain cells, forms the brain-CSF barrier, and is important in central nervous system immune cell surveillance.
Still, relatively little is known about what biological and physiological factors regulate the CP under healthy conditions. CSF production in humans is thought to be diurnally regulated, and recent evidence in animal models demonstrating strong clock components in the CP is in line with circadian-dependent transcriptional regulation. Moreover, CSF movement and clearance is regulated by both sleep and circadian rhythms.
However, CP function and CSF dynamics are altered with age and in the setting of Alzheimer’s disease (AD), where sleep and circadian disruption often co-occur. We hypothesized that the CP is functionally regulated by sleep and circadian rhythms, and that this regulation would be disrupted with old age and with AD.
To test this, we collected CP tissue from wild-type C57BL/6 mice at 3 months (young), 12-14 months (aged), and from 12–14-month-old J20 mice (B6.Cg-Zbtb20Tg(PDGFBAPPSwInd)20Lms/2Mmjax) as a model of amyloidopathy (AD mice). Tissue was collected at opposite circadian times (Zeitgeber +6 and +18) to coincide with the middle of light and dark phases of the day. We performed bulk RNA sequencing on the tissue to examine the transcriptional profile across the day in the three conditions (young, old, AD).
We observed that in young healthy mice, circadian rhythms are the main governing factors driving changes in gene expression in the CP. Circadian-dependent gene changes are enriched for inflammatory and immune pathways in young mice, but in old mice shift to prioritizing membrane transport, vesicular function and ion channel regulation. Alternatively in mice with amyloid accumulation circadian regulation is all but lost in the CP.
Our data suggest age-related circadian shifts in inflammatory regulation, and CSF homeostasis at the CP that may drive disease processes. However, when pathology is present, in the case of amyloid, circadian regulation at the CP is no longer functional and likely exacerbates existing neurodegeneration.
Research Funding Sources: Dr Jansson’s fellowship was funded by the Neurological Foundation of New Zealand, research costs were funded by grants awarded to Professor Iliff from the NIH, NIA, and the Alzheimer’s Disease Research Centre (ADRC), University of Washington.
Deidre Jansson1,2,3, Ryan O’Boyle2,3, Mathew Sevao2,3, Taylor Pedersen2,3, Ron Vered2,3, Elizabeth Gino2,3, Molly Braun2,3, Samantha Keil2,3, Jeffrey Iliff2,3
1University of Auckland, Auckland, New Zealand, 2University of Washington, Seattle, USA,
3VA Puget Sound Health Care System, Seattle, USA
The choroid plexus (CP) is a highly vascularized stromal tissue located in each of the four brain ventricles. Encased by ciliated epithelial cells, the CP is responsible for the majority of cerebrospinal fluid (CSF) production in the brain. The CP also delivers trophic factors to surrounding brain cells, forms the brain-CSF barrier, and is important in central nervous system immune cell surveillance.
Still, relatively little is known about what biological and physiological factors regulate the CP under healthy conditions. CSF production in humans is thought to be diurnally regulated, and recent evidence in animal models demonstrating strong clock components in the CP is in line with circadian-dependent transcriptional regulation. Moreover, CSF movement and clearance is regulated by both sleep and circadian rhythms.
However, CP function and CSF dynamics are altered with age and in the setting of Alzheimer’s disease (AD), where sleep and circadian disruption often co-occur. We hypothesized that the CP is functionally regulated by sleep and circadian rhythms, and that this regulation would be disrupted with old age and with AD.
To test this, we collected CP tissue from wild-type C57BL/6 mice at 3 months (young), 12-14 months (aged), and from 12–14-month-old J20 mice (B6.Cg-Zbtb20Tg(PDGFBAPPSwInd)20Lms/2Mmjax) as a model of amyloidopathy (AD mice). Tissue was collected at opposite circadian times (Zeitgeber +6 and +18) to coincide with the middle of light and dark phases of the day. We performed bulk RNA sequencing on the tissue to examine the transcriptional profile across the day in the three conditions (young, old, AD).
We observed that in young healthy mice, circadian rhythms are the main governing factors driving changes in gene expression in the CP. Circadian-dependent gene changes are enriched for inflammatory and immune pathways in young mice, but in old mice shift to prioritizing membrane transport, vesicular function and ion channel regulation. Alternatively in mice with amyloid accumulation circadian regulation is all but lost in the CP.
Our data suggest age-related circadian shifts in inflammatory regulation, and CSF homeostasis at the CP that may drive disease processes. However, when pathology is present, in the case of amyloid, circadian regulation at the CP is no longer functional and likely exacerbates existing neurodegeneration.
Research Funding Sources: Dr Jansson’s fellowship was funded by the Neurological Foundation of New Zealand, research costs were funded by grants awarded to Professor Iliff from the NIH, NIA, and the Alzheimer’s Disease Research Centre (ADRC), University of Washington.
