Cerebrovascular Smooth Muscle Cell Surface Fibrillar Aβ: Alteration of the Proteolytic Environment in the Cerebral Vessel Wall

Nostrand, William E. Van; Melchor, Jerry P.; Wagner, Matthew R.; Davis, James Earl

doi:10.1111/j.1749-6632.2000.tb06354.x

Cited by 19 publications

(7 citation statements)

References 36 publications

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“…Moreover, Aβ fibrillation activates an apoptotic pathway in the cerebrovascular smooth muscle cells, leading to cell death (Van Nostrand et al, 2000b). The combination of the cell death and the anticoagulant environment induced by Aβ fibrils in the vessel wall are probably major contributors to the hemorrhages in HCHWA-D patients.…”

Section: Aβ Fibril Assembly At Cell Surfacesmentioning

confidence: 99%

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Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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Hereditary cerebral hemorrhage with amyloidosis – Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the ‘Dutch mutation’. Amyloid β, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid β cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid β accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid β metabolism due to mutations like the ‘Dutch’ provides us with a better understanding of amyloid β toxicity, also in other amyloid β diseases like sporadic cerebral amyloid angiopathy and Alzheimer’s disease.

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Section: Aβ Fibril Assembly At Cell Surfacesmentioning

confidence: 99%

“…After Aβ fibrillation, sAPP is able to bind to the Aβ fibrils at the smooth muscle cell surface (Van Nostrand et al, 2000a). The binding of APP leads to the presence of the Kunitz-type protease inhibitor (KPI) domain, which is part of most of the APP isoforms.…”

Section: Aβ Fibril Assembly At Cell Surfacesmentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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“…Vascular amyloid is composed predominantly of Ab1-40, which is produced following proteolytic cleavage of the amyloid precursor protein (APP). In addition to resulting in degeneration of cerebrovascular smooth muscle and endothelial cells (Davis-Salinas et al, 1995;Van Nostrand et al, 2000), CAA inhibits angiogenesis, impairs vascular tone, and decreases total cerebral blood flow (Beckmann et al, 2003;Paris et al, 2004;Shin et al, 2007). Clinically, the degree of CAA severity correlates with cerebral hypoperfusion, increased risk of microhemorrhage, and degree of cognitive impairment (Pfeifer et al, 2002;Schrag et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

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“…33,34 In vitro data further suggest that Aβ promotes urokinase-type plasmin activator expression and plasminogen activation in human cerebrovascular smooth muscle cells. 35,36 Although the APP23-tg mouse model of CAA is at greater risk for spontaneous vascular leakage with development of cMBs and lobar ICH, we observed no ICH after r-tPA treatment outside the infarct area. This difference from a previous study using the same mouse model may be related to the different interval between r-tPA treatment and analysis (24 hours in the present study versus 10 days in Winkler et al 37 ).…”

Section: Discussionmentioning

confidence: 55%

Thrombolysis in Experimental Cerebral Amyloid Angiopathy and the Risk of Secondary Intracerebral Hemorrhage

Reuter

Grudzenski

Chatzikonstantinou

et al. 2014

Stroke

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Background and Purpose-Intracerebral hemorrhage (ICH) is the most adverse event of thrombolysis in ischemic stroke.Cerebral amyloid angiopathy increases the risk for spontaneous lobar ICH. Although thrombolysis may be performed in cerebral amyloid angiopathy-affected patients, there is still little knowledge available on the risk for secondary ICH. Methods-We investigated the effect of recombinant tissue-type plasminogen activator on experimental ischemic stroke in APP23 transgenic mice (n=18) and wild-type littermates (n=15). Focal ischemic stroke was induced in 26-month-old mice by temporal middle cerebral artery occlusion (filament model), followed by treatment with 10 mg/kg recombinant tissue-type plasminogen activator. Twenty-four hours later, a functional score was assessed and the mice were euthanized for histological analysis. ICH was classified as grades 1 to 3 depending on severity. Results-The groups did not differ regarding mortality (P=0.67) and functional deficit (P=0.18). Compared with wild-type mice, the APP23 genotype was associated with a higher appearance for ICH in the infarct area (P=0.05). ICH severity grades 2 and 3 correlated significantly with infarct size (P=0.004 and 0.008, respectively). Conclusions-The APP23 genotype was not associated with increased mortality or worse functional outcome. Our results suggest an increased risk for ICH in the cerebral amyloid angiopathy-affected brain; however, no ICH was observed outside the ischemic area. (Stroke. 2014;45:2411-2416.)

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Cerebrovascular Smooth Muscle Cell Surface Fibrillar Aβ: Alteration of the Proteolytic Environment in the Cerebral Vessel Wall

Cited by 19 publications

References 36 publications

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Thrombolysis in Experimental Cerebral Amyloid Angiopathy and the Risk of Secondary Intracerebral Hemorrhage

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