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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

Cerebral amyloid angiopathy occurs after stroke, but the mechanism underlying the initial amyloid-β deposition is not fully understood. This study investigates whether overexpression of fibronectin and its receptor, integrin-α5, induces the perivascular deposition of cerebrospinal fluid-derived amyloid-β after stroke in young and aged animals. We found that stroke impaired the bulk flow of cerebrospinal fluid into the brain parenchyma and further showed that perivascular amyloid-β deposition was enhanced in aged animals with stroke, which colocalized with integrin-α5 in the basement membrane. Furthermore, we found that stroke dramatically increased the cortical levels of fibronectin and integrin-α5, with further increases in integrin-α5 in aged animals with stroke, fibronectin bound amyloid-β in vitro, and fibronectin administration increased amyloid-β deposition in vivo. Finally, aging and stroke impaired performance on the Barnes maze. These results indicate that fibronectin induces the perivascular deposition of amyloid-β and that increased integrin-α5 further "primes" the aged brain for amyloid-β binding. This provides a novel molecular and physiological mechanism for perivascular amyloid-β deposition after stroke, particularly in aged individuals.

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