Abstract
Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-β induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-β induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-β receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-β stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix production. Finally, in stroke patients, we found that serum TGF-β levels correlated with poorer functional outcomes, suggesting that serum levels may act as a biomarker for functional recovery. These results support a potential new treatment strategy to enhance recovery in elderly stroke patients.
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Funding
This study was partially supported by funding provided to the Texas Alzheimer’s Research and Care Consortium (TARCC) by the state of Texas, through the Texas Council on Alzheimer’s Disease and Related Disorders (to A.U.), and NIH/NIA RF1AG057576 (to A.U.), and by the NIH/NINDS R01NS094543 (to L.D.M.). Fellowship support was provided by the American Heart Association via AHA17PRE33410369 (to M.D.H.) and the NIH via 4TL1TR000369-10 (to M.D.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
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Please see the Online Supplement for additional supplemental data. Table S1 provides information on the primer sequences used for all qPCR data. Table S2 shows additional statistical values that pertain to the qPCR data. Table S3 contains detailed results of the multivariable modeling of serum TGF-β on neurological deterioration and function at discharge in human stroke patients.
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Howe, M.D., Furr, J.W., Munshi, Y. et al. Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke. GeroScience 41, 543–559 (2019). https://doi.org/10.1007/s11357-019-00118-7
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DOI: https://doi.org/10.1007/s11357-019-00118-7