Glymphatic Clearance of Abeta is Impaired by Fibronectin in the Basement Membrane

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

PROJECT SUMMARY Cerebral amyloid angiopathy (CAA) is a neurodegenerative condition that is characterized by the deposition of toxic amyloid-? aggregates in the basement membrane (BM) of brain arterioles and capillaries, leading to recurrent stroke, cerebral hemorrhage and cognitive decline in patients. CAA may develop in part from impaired clearance of amyloid-? from the BM blood vessels after stroke. The recently discovered glymphatic system facilitates the clearance of amyloid-? by enabling the bulk flow of cerebrospinal fluid (CSF) within the BM of cerebral vessels. It is not known whether BM fibrosis alters the clearance of amyloid-? through the glymphatic system. We hypothesize that stroke induces global perivascular reactive astrocytosis and fibrosis via enhanced systemic TGF-? signaling, and that this is increased with aging. It is further hypothesized that BM fibrosis impairs glymphatic flow, leading to reduced clearance of amyloid-?. ?? assess the global effects of stroke on the BM, glymphatic flow and amyloid-? clearance, distal middle cerebral artery occlusion (pDMCAO) will be performed in young and aged mice. We will examine if stroke alters BM composition via increased TGF-? signaling in perivascular astrocytes in mice, and determine whether inhibition of TGF-? signaling in astrocytes prevents these changes and enhances the clearance of amyloid-?. The effect of stroke-induced fibrosis on glymphatic flow and clearance of injected amyloid-? will be evaluated. Preliminary data indicates that unilateral stroke in young mice induces profound changes in the contralateral cortex, including enhanced TGF-? (Smad2/3) signaling, reactive astrocytosis, and BM fibronectin deposition. Furthermore, these changes were associated with reduced penetration of injected CSF dextran tracers, indicating impaired glymphatic flow. Finally, injected CSF amyloid- ? exhibited a higher association with the BM after stroke. Based on these data and work from our laboratory showing enhanced gliosis in aged animals after stroke, it is expected that stroke will further impair glymphatic amyloid-? clearance in aged animals due to increased fibrosis, leading to progressive cognitive decline. As a final proof of concept, we will utilize a mouse model of CAA to determine if stroke-induced changes in the BM leads to accelerated CAA pathology. This research is significant as it identifies BM fibrosis as a novel mechanism of glymphatic impairment and amyloid-? accumulation, providing an elusive ?driving force? in the development of CAA that is translationally relevant in understanding how disease progresses in elderly individuals, as well as those suffering from ischemic stroke. If successful, this study will identify TGF-? inhibition as a potential disease- modifying therapy to reduce fibrosis, enhance glymphatic flow and reduce CAA.