Abstract WP438: The Role of Transforming Growth Factor-beta in Post-Stroke Glymphatic Impairment

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Abstract

Introduction: The recently discovered glymphatic system may protect the brain from dementia by clearing toxic amyloid-β (Aβ) along the basement membrane (BM) via bulk flow of cerebrospinal fluid (CSF). It is not known whether stroke impairs glymphatic flow, or how this might occur. Previous work has shown that stroke enhances astrocytic transforming growth factor-β (TGF-β) signaling, which could increase the expression of pro-fibrotic BM proteins such as fibronectin. BM fibrosis may obstruct glymphatic flow after stroke, driving Aβ accumulation and neurodegenerative disease in stroke survivors.

Hypothesis: I hypothesize that stroke induces BM fibrosis via enhanced TGFβ-Smad2 signaling in perivascular astrocytes, impairing glymphatic flow.

Methods: To test this hypothesis, the glymphatic influx of CSF tracer in mice following stroke or TGF-β treatment (ICV, 500 ng) was assessed. TGF-β signaling was measured as Smad2 phosphorylation. Brain expression of fibronectin and GFAP (astrocytes) were assessed by western blot and immunohistochemistry.

Results: Stroke impaired the glymphatic distribution of FITC-dextran and FITC-Aβ bilaterally (Fig. 1). TGF-β treatment also inhibited glymphatic distribution, measured by reduced 14C-Inulin uptake (38 fold-reduction, p < .05). Increased fibronectin (5.5 ± 0.7 fold-increase) and GFAP (2.3 ± .2 fold-increase) expression was found after stroke (p < .05), localized to the glial scar and around vessels bilaterally. Finally, Smad2 phosphorylation was increased in cortex contralateral to injury (2.5 ± 0.2 fold, p < .01).

Conclusion: The present study shows that stroke impairs glymphatic flow, which may be mediated through increased TGF-β signaling and global BM fibrosis. This could impair the clearance of Aβ, leading to dementia in stroke survivors. TGF-β inhibition can rescue post-stroke fibrosis, glymphatic flow and Aβ clearance, presenting a novel therapeutic target for post-stroke dementia.

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