Requirement of brain interleukin33 for aquaporin4 expression in astrocytes and glymphatic drainage of abnormal tau
Authors: Colin Carlock
April Ross
Joao Quevedo
William Glass 2nd
Jean Wu
Ines Moreno-Gonzalez
Yahuan Lou
Junbo Shim
Tatiana Barichello
Journal: Molecular Psychiatry (2021)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Aquaporin4; glymphatic drainage; IL33; astrocytes; tauopathy
Affiliations: Department of Diagnostic Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, 77054, USA., Department of Neurology, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Mitchell Center for Alzheimer's Disease and Related Brain Disorders, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Networking Research Center on Neurodegenerative Diseases (CIBERNED), Department of Cell Biology, Facultad Ciencias, Universidad de Malaga, Malaga, Spain., Department of Pathology, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Department of Psychiatry and Behavioral Sciences, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77054, USA., Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil., Department of Diagnostic Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, 77054, USA. .

Abstract:  Defective aquaporin4 (AQP4)-mediated glymphatic drainage has been linked to tauopathy and amyloid plaque in Alzheimer's disease. We now show that brain interleukin33 (IL33) is required for regulation of AQP4 expression in astrocytes, especially those at neuron-facing membrane domain (n-AQP4). First, IL33-deficient (Il33-/-) mice showed a loss of n-AQP4 after middle age, which coincided with a rapid accumulation of abnormal tau in neurons and a reduction in drainage of abnormal tau to peripheral tissues. Second, injection of recombinant IL33 induced robust expression of AQP4 at perivascular endfoot (p-AQP4) of astrocytes, but not n-AQP4, in Il33-/- brains. Although the increased p-AQP4 greatly accelerated drainage of intracerebroventricularly injected peptides, it did not substantially accelerate drainage of abnormal tau. These results suggest that p-AQP4 drives overall convective flow toward perivenous space, i.e., glymphatics, whereas n-AQP4 may generate an aqueous flow away from neurons to remove neuronal wastes, e.g., abnormal tau. We have previously shown the role of brain IL33 in DNA repair and autophagy in neurons with oxidative stress. Now, we show that IL33 deficiency also impairs glymphatic drainage. Defects in those mechanisms together may lead to chronic neurodegeneration and tauopathy at old age in IL33-deficient mice. 

Retracted: No

PubPeer comments:
 In this manuscript, the authors wrote that  Unless specifically stated, five female mice, which were randomly selected from 10, were used for an experimental or control group. These sample sizes were estimated based on previous experiences. Because there was no actual statistical power and sample size calculation, it is impossible for other researchers to evaluate the rigor of this study. Almost all data supporting the conclusion are based on descriptive IHC data and the unreasonable quantification method. For example, how can the authors get such many data points from only N=5 mice for Figure 2C? It is clear that the authors inappropriately performed the statistical analysis as if each brain section is each mouse. There should be one data point from one mouse. Considering each brain section as if it is each mouse is a fundamentally flawed analysis. ,