scholarly journals Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers

2021 ◽  
Author(s):  
Emma L Anderson ◽  
Dylan M Williams ◽  
Venexia Walker ◽  
Neil M Davies
Keyword(s):  
Cognitive Impairment ◽  
Matrix Metalloproteinase ◽  
Drug Targets ◽  
Cyclophilin A ◽  
Matrix Metalloproteinase 9 ◽  
Synaptic Function ◽  
Polygenic Risk Score ◽  
Alzheimers Disease ◽  
Score Analysis ◽  
Metalloproteinase 9

AbstractTherapeutic targets for halting the progression of Alzheimers disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the cyclophilin A matrix metalloproteinase-9 (CypA MMP9) pathway in the cerebrospinal fluid, leading to an accelerated breakdown of the blood brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence that CypA or MMP9 affected the risk of Alzheimers disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in APOE4 carriers.

Cyclophilin A and matrix metalloproteinase-9: Their relationship, association with, and diagnostic relevance in stable coronary artery disease

Vascular ◽  
2019 ◽  
Vol 28 (2) ◽  
pp. 212-221 ◽  
Author(s):  
Hala F Ebrahim ◽  
Fatma F Abdel Hamid ◽  
Mohamed A Haykal ◽  
Ahmed F Soliman
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Matrix Metalloproteinase ◽  
Stable Coronary Artery Disease ◽  
Cyclophilin A ◽  
Matrix Metalloproteinase 9 ◽  
Artery Disease ◽  
Circulating Levels ◽  
Metalloproteinase 9 ◽  
Normal Controls

Objectives Data about the circulating levels of cyclophilin A and matrix metalloproteinase-9 in stable coronary artery disease are contradictory. Moreover, their relationship in this disease is not established yet. Thus, this study was designed to assess the relationship between the circulating levels of cyclophilin A and matrix metalloproteinase-9 in coronary artery disease patients with and without type 2 diabetes mellitus (T2DM). Methods Serum levels of cyclophilin A, matrix metalloproteinase-9, and high sensitive C-reactive protein (hsCRP) along with fasting blood glucose, glycated hemoglobin, serum lipids, and the anthropometric parameters were measured in 120 participants who were divided equally into four groups (i) normal controls, (ii) T2DM patients, (iii) stable coronary artery disease patients with T2DM, and (iv) stable coronary artery disease patients without T2DM. Results Levels of cyclophilin A and matrix metalloproteinase-9 were significantly elevated in sera of coronary artery disease patients with and without T2DM compared to normal controls and T2DM patients. In multiple linear regression models, only cyclophilin A was observed in the final model where it explained the 24.9% variability of matrix metalloproteinase-9. Additionally, high circulating levels of cyclophilin A and matrix metalloproteinase-9 were associated with an increased risk of developing stable coronary artery disease. Finally, the diagnostic efficacy of cyclophilin A and matrix metalloproteinase-9 to discriminate stable coronary artery disease patients with and without T2DM from subjects without coronary artery disease was found to be higher than that of hsCRP. Conclusion Serum level of cyclophilin A might be a determinant factor of matrix metalloproteinase-9 level; both may contribute to the pathogenesis of stable coronary artery disease and they appear to be valuable diagnostic biomarkers of stable coronary artery disease with and without T2DM.

scholarly journals Matrix metalloproteinase-9 blood level as a predictor of post-stroke cognitive impairment

2018 ◽  
Vol 20 (2) ◽  
pp. 48-54
Author(s):  
D P Kalinsky ◽  
V Yu Lobzin ◽  
I G Ulyanov
Keyword(s):  
Ischemic Stroke ◽  
Cognitive Impairment ◽  
Matrix Metalloproteinase ◽  
Recovery Period ◽  
Speech Disorders ◽  
Matrix Metalloproteinase 9 ◽  
Early Recovery ◽  
Acute Period ◽  
Post Stroke ◽  
Metalloproteinase 9

Ischemic stroke is one of the leading causes of disability of the population. Among the consequences of stroke besides motor, speech disorders, the most important cause of cognitive impairments, it’s frequency is variable between 25-40%. Post-stroke cognitive disorders are pathogenetically heterogeneous conditions. The nature, modality and severity are determined by the clinical subtype of it’s development. So, cognitive impairment most often can be a consequence of a strategic infarcts, multi-infarct damage, decompensation of chronic cerebrovascular pathology against the background of an acute condition or neurodegenerative process that existed earlier and diagnosed before the appearance of any signs of stroke. In addition, the subtype of ischemic stroke also matters. In stroke, a family of zinc-binding proteolytic enzymes, in particular matrix metalloproteinase-9, plays a significant role in the development of damage of the brain tissue, which is of great importance in the reconstruction of the extracellular matrix. A high serum concentration of metalloproteinase-9 increases the severity of ischemic damage, the severity of the stroke and worsens the functional outcome of the disease. In addition, metalloproteinase-9 is also considered as a biomarker for Alzheimer’s disease, since it acts as a proteolytic enzyme, which, along with neprilizine, cleaves the amyloid protein. The results of a survey of 135 patients in the acute and early recovery period of ischemic stroke are presented. The level of metalloproteinase-9 and cognitive impairment have been studied on 1-2 and 21-22 days of the disease. It was found that a higher level of metalloproteinase-9 in blood plasma reflects a high probability of post-stroke cognitive impairment at the end of an acute period of ischemic stroke. The increase in metalloproteinase-9 did not depend on the localization of the focus of the stroke and its volume. Thus, metalloproteinase-9 investigation in the acute period of the ischemic stroke can predict the development of post-stroke cognitive decline.

scholarly journals Hyperhomocysteinemia-Induced Gene Expression Changes in the Cell Types of the Brain

ASN NEURO ◽  
2017 ◽  
Vol 9 (6) ◽  
pp. 175909141774229 ◽  
Author(s):  
Erica M. Weekman ◽  
Abigail E. Woolums ◽  
Tiffany L. Sudduth ◽  
Donna M. Wilcock
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Cognitive Impairment ◽  
Matrix Metalloproteinase ◽  
Inflammatory Marker ◽  
Neuronal Cells ◽  
Specific Effect ◽  
Vascular Cognitive Impairment ◽  
Matrix Metalloproteinase 9 ◽  
Metalloproteinase 9

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer’s disease and vascular cognitive impairment and dementia.

P3-077: Matrix metalloproteinase 9 (MMP-9) in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI)

2015 ◽  
Vol 11 (7S_Part_14) ◽  
pp. P646-P647
Author(s):  
Pawel Muszynski ◽  
Magdalena Groblewska ◽  
Barbara Mroczko ◽  
Marzena Zboch ◽  
Renata Borawska ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 9 ◽  
Metalloproteinase 9
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