Protease nexin-2/amyloid β-protein precursor limits cerebral thrombosis

Xu, Feng; Davis, James Earl; Miao, Jianting; Previti, Mary Lou; Romanov, Galina; Ziegler, Kelly; Nostrand, William E. Van

doi:10.1073/pnas.0507798102

Cited by 50 publications

(66 citation statements)

References 52 publications

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“…Proteolytic activation of trypsinogen 4 produces an active enzyme identical in protein sequence and catalytic properties to pancreatic mesotrypsin; in the context of the brain, this enzyme has also been referred to as trypsin 4, trypsin IV, or brain trypsin (62)(63)(64). The inhibitory activity of sAPP/protease nexin 2 plays a key role in regulating cerebral hemostasis and preventing thrombosis during cerebral vascular injury (65)(66)(67). Thus, in the brain as elsewhere, by attacking and cleaving the inhibitory Kunitz domain of sAPP/ protease nexin 2, mesotrypsin may modulate the procoagulant/ anticoagulant balance.…”

Section: Discussionmentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-␤ peptides. The major splice isoforms of APP expressed by most tissues contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg 15 -Ala 16 reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are coexpressed in a number of tissues, we suggest that processing by mesotrypsin may ablate the protease inhibitory function of APP/protease nexin 2 in vivo and may also modulate other activities of APP/protease nexin 2 that involve the Kunitz domain.Mesotrypsin is a human trypsin encoded by the PRSS3 gene found on chromosome 9p13 (1). Normal expression of PRSS3 is restricted to pancreas, brain, and, to a lesser extent, small intestine and colon (2-4); additionally, PRSS3 appears to be transcriptionally up-regulated with cancer progression in epithelial cancers, including lung (5), colon (6), and prostate. Mesotrypsin exhibits substantially different specificity from other trypsins toward protein substrates. It fails to activate pancreatic zymogens and also shows reduced capacity to degrade trypsinogens (7). Compared with other trypsins, it is significantly compromised in its ability to cleave protease-activated receptors (8 -10). Despite limited activity toward these classic trypsin substrates, mesotrypsin displays enhanced catalytic activity compared with other trypsins in the cleavage of certain specific protein substrates, most notably several canonical protease inhibitors (7, 11).The "canonical" inhibitors of serine proteases, named for a protease-binding loop of highly characteristic backbone conformation (12, 13), fulfill the paradoxical function of binding to a protease in a substrate-like manner yet acting as an inhibitor rather than an ordinary substrate. These inhibitors, representing at least 18 different convergently evolved protein families (14, 15), inhibit their cognate proteases via the "Laskowski mechanism," in which inhibitors act as highly specific, limited proteolysis substrates for target enzymes (14, 16). They bind so as to position a specific peptide bond, the "reactive si...

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Section: Discussionmentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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“…Some of the toxic effects attributed to amyloid include decrease in the expression of the tight junction proteins, 9 increase in the expression of matrix metalloproteases, 6,9,29 impairment of the regulation of cerebral blood flow, 6,9,30 impairment of endothelial function, 9,18,29 interference with the general homeostatic mechanisms of the aging brain, 6,31,32 enhancement of BBB disruption, 6 promotion of inflammation, 6 oxidative stress, 29,32 and antithrombotic effects. 29,31,33 Aβ can cause abnormal vascular reactivity without vessel deposition or vessel wall dysfunction.…”

Section: Strokementioning

confidence: 99%

Prognostic Value of Plasma β-Amyloid Levels in Patients With Acute Intracerebral Hemorrhage

Martí‐Fàbregas

Delgado‐Mederos

Marín

et al. 2014

Stroke

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Background and Purpose— It has been proposed that the deposition of the β-amyloid peptide (Aβ) in the brain parenchyma and brain blood vessels has deleterious effects. We tested the hypothesis that the levels of plasma Aβ are related to the outcome in patients with intracerebral hemorrhage. Methods— In a multicenter study, we prospectively included patients with spontaneous intracerebral hemorrhage within the first 24 hours after onset. At admission, we measured plasma Aβ40 and Aβ42 levels using ELISA techniques. Also, we recorded age, sex, vascular risk factors, National Institutes of Health Stroke Scale score, presence of intraventricular hemorrhage, localization, cause, and volume of the hematoma. We obtained the modified Rankin scale and defined a unfavorable outcome as modified Rankin scale >2 at 3 months. Bivariate and multivariate regression analyses were performed. Results— We studied 160 patients (mean age, 73.8±11.3 years; 59.4% of them were men). A favorable outcome was observed in 64 (40%) of the patients. In the bivariate analyses, unfavorable outcome was associated with high age, female sex, diabetes mellitus, presence of intraventricular hemorrhage, high blood glucose, high National Institutes of Health Stroke Scale score, high volume, and high plasma levels of Aβ42 and Aβ40. The multivariate analysis showed that increased age (odds ratio, 1.07; 95% confidence interval, 1.035–1.21; P <0.0001), high admission National Institutes of Health Stroke Scale score (odds ratio, 1.29, 95% confidence interval, 1.17–1.42; P <0.0001), presence of diabetes mellitus (odds ratio, 4.15; 95% confidence interval, 1.21–14.1; P =0.02), and Aβ42 levels >9.7 pg/mL (odds ratio, 4.11; 95% confidence interval, 1.65–10.1; P =0.02) were independently associated with an increased likelihood of an unfavorable outcome. Conclusions— High levels of plasma Aβ42 in patients with acute intracerebral hemorrhage are associated with a poor functional prognosis.

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“…The Aβ peptide is proteolytically derived from its parent molecule, the amyloid-β protein precursor (AβPP). AβPP is an integral membrane protein that has been implicated in blood clotting [7] and as a regulator of neural plasticity and post-injury repair [8]. Aβ peptides are produced as a result of sequential cleavage of AβPP by enzymes known as the β-secretase (also known as β-site AβPP cleavage enzyme or BACE) and γ-secretase, respectively.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost

Martins

Kanagasingam

2010

JAD

100

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Alzheimer's disease (AD) is the most common form of dementia and is characterized clinically by a progressive decline in memory, learning and executive function and neuropathologically by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive pre-mortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred, hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments.While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular based screening test for AD.

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Protease nexin-2/amyloid β-protein precursor limits cerebral thrombosis

Cited by 50 publications

References 52 publications

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Prognostic Value of Plasma β-Amyloid Levels in Patients With Acute Intracerebral Hemorrhage

Ocular Biomarkers for Early Detection of Alzheimer's Disease

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