Elevated Expression of Urokinase Plasminogen Activator in Rodent Models and Patients With Cerebral Amyloid Angiopathy

Objective: To study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA) in a rat model for CAA type-I (rTg-DI) and in patients with sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA). Additionally, to investigate the potential of uPA to serve as a diagnostic biomarker of CAA in cerebrospinal fluid (CSF) from patients with sCAA and D-CAA.Methods: We studied the expression of uPA mRNA by qPCR and co-localization of uPA with amyloid-β (Aβ) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared to wild type (WT) rats and in an sCAA patient and control subject using immunohistochemistry. CSF levels of uPA were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and D-CAA patients and controls, using enzyme-linked immunosorbent assays (ELISA).Results: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient, but not in WT rats or a non-CAA human control. uPA expression was highly co-localized with microvascular Aβ deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular CAA deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared to WT rats. CSF uPA levels were elevated in rTg-DI rats compared to WT rats (p=0.03), and in two separate, independent groups of sCAA patients compared to controls (after adjustment for age of subjects, p=0.05 and p=0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p=0.09 and p=0.44).Conclusion: uPA expression appears linked to the onset of CAA in rTg-DI rats. Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA. No differential expression levels of uPA in CSF of (a)symptomatic D-CAA patients were discovered. These studies also further support the use of rTg-DI rat models as a useful preclinical model for the study of human CAA type-I.