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

2021 ◽  
Author(s):  
Marc Vervuurt ◽  
Xiaoyue Zhu ◽  
Joseph Schrader ◽  
Anna de Kort ◽  
Tainá Marques ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Urokinase Plasminogen Activator ◽  
Preclinical Model ◽  
Amyloid Angiopathy ◽  
Type I ◽  
Cerebral Vasculature ◽  
Cerebral Amyloid ◽  
Upa Mrna

Abstract 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.

scholarly journals Urokinase plasminogen activator (uPA) as a novel biomarker for cerebral amyloid angiopathy

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Marc Vervuurt ◽  
Anna M. de Kort ◽  
Floris HBM Schreuder ◽  
Catharina J.M. Klijn ◽  
H. Bea Kuiperij ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Cerebral Amyloid Angiopathy ◽  
Urokinase Plasminogen Activator ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

scholarly journals Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces

2015 ◽  
Vol 36 (3) ◽  
pp. 576-580 ◽  
Author(s):  
Susanne J van Veluw ◽  
Geert Jan Biessels ◽  
Willem H Bouvy ◽  
Wim GM Spliet ◽  
Jaco JM Zwanenburg ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Resonance Imaging ◽  
Centrum Semiovale ◽  
Tissue Sections ◽  
Cortical Areas ◽  
Cerebral Amyloid

Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3–7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity.

scholarly journals Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

2018 ◽  
Vol 135 (5) ◽  
pp. 671-679 ◽  
Author(s):  
Zane Jaunmuktane ◽  
Annelies Quaegebeur ◽  
Ricardo Taipa ◽  
Miguel Viana-Baptista ◽  
Raquel Barbosa ◽  
...  
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab

Stroke ◽  
2021 ◽  
Author(s):  
Lukas Sveikata ◽  
Andreas Charidimou ◽  
Anand Viswanathan
Keyword(s):  
Clinical Trials ◽  
Alzheimer Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
High Rate ◽  
Amyloid Angiopathy ◽  
Cerebrovascular Pathology ◽  
Cerebral Amyloid

We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy’s efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.

Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation

2015 ◽  
Vol 50 (1) ◽  
pp. 1-7 ◽  
Author(s):  
María Carmona-Iragui ◽  
Ana Fernández-Arcos ◽  
Daniel Alcolea ◽  
Fabrizio Piazza ◽  
Estrella Morenas-Rodriguez ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Amyloid Pet ◽  
Cerebral Amyloid

MEMANTINE ATTENUATES VASCULAR AMYLOID β DEPOSITS AND SPONTANEOUS HEMORRHAGES IN MOUSE MODELS OF CEREBRAL AMYLOID ANGIOPATHY

2017 ◽  
Vol 13 (7) ◽  
pp. P917-P918 ◽  
Author(s):  
Yasuteru Inoue ◽  
Mitsuharu Ueda ◽  
Teruaki Masuda ◽  
Yohei Misumi ◽  
Taro Yamashita ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid

Pathogenic Effects of Cerebral Amyloid Angiopathy Mutations in the Amyloid β-Protein Precursor

2002 ◽  
Vol 977 (1) ◽  
pp. 258-265 ◽  
Author(s):  
WILLIAM E. NOSTRAND ◽  
JERRY P. MELCHOR ◽  
GALINA ROMANOV ◽  
KELLY ZEIGLER ◽  
JUDIANNE DAVIS
Keyword(s):  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Cerebral Amyloid ◽  
Pathogenic Effects

scholarly journals Endothelial expression of human APP leads to cerebral amyloid angiopathy in mice

2020 ◽  
Author(s):  
Yuriko Tachida ◽  
Saori Miura ◽  
Rie Imamaki ◽  
Naomi Ogasawara ◽  
Hiroyuki Takuwa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Angiopathy ◽  
Disease Mechanisms ◽  
Age Dependent ◽  
Cerebral Amyloid ◽  
The Brain

AbstractThe deposition of amyloid β (Aβ) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in more than 90% of Alzheimer’s disease (AD) patients. The presence of such CAA pathology is not as evident, however, in most mouse models of AD, thereby making it difficult to examine the contribution of CAA to the pathogenesis of AD. Since blood levels of soluble amyloid precursor protein (sAPP) in rodents are less than 1% of those in humans, we hypothesized that endothelial APP expression would be markedly lower in rodents, thus providing a reason for the poorly expressed CAA pathology. Here we generated mice that specifically express human APP770 in endothelial cells. These mice exhibited an age-dependent robust deposition of Aβ in brain blood vessels but not in the parenchyma. Crossing these animals with APP knock-in mice led to an expanded CAA pathology as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results show that both neuronal and endothelial APP contribute cooperatively to vascular Aβ deposition, and suggest that this mouse model will be useful for studying disease mechanisms underlying CAA and for developing novel AD therapeutics.

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