Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) pathology is characterized by A beta peptide-containing plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, extensive neuritic degeneration, and distinct neuron loss. We generated several transgenic mouse lines expressing the human amyloid precursor protein (APP751) containing the AD-linked KM670/671NL double mutation (Swedish mutation) under the control of a neuron-specific Thy-1 promoter fragment. In the best APP-expressing line (APP23), compact A beta deposits can be detected at 6 months of age. These plaques dramatically increase with age, are mostly Congo Red positive, and accumulate typical plaque-associated proteins such as heparansulfate proteoglycan and apolipoprotein E. Activated astrocytes and microglia indicative of inflammatory processes reminiscent of AD accumulate around the deposits. Furthermore, plaques are surrounded by enlarged dystrophic neurites as visualized by neurofilament or Holmes-Luxol staining. Strong staining for acetylcholinesterase activity is found throughout the plaques and is accompanied by local distortion of the cholinergic fiber network. All congophilic plaques contain hyperphosphorylated tau reminiscent of early tau pathology. Modern stereologic methods demonstrate a significant loss of neurons in the hippocampal CA1 region, correlating with an increasing A beta plaque load. Interestingly, APP23 mice develop cerebral amyloid angiopathy in addition to amyloid plaques even though the APP transgene is only expressed in neurons. Crossbreeding of APP23 mice with transgenic mice carrying AD-linked presenilin mutations but not wild-type presenilin resulted in enhanced formation of pathology. In conclusion, our APP transgenic mice present many pathologic features, similar to those observed in AD and therefore offer excellent tools for studying the contribution of A beta to AD pathogenesis.
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PMID:Transgenic mouse models of Alzheimer's disease. 1091 65

Alzheimer's disease is a primary degenerative dementia and is not considered to be of vascular origin. Furthermore, severe cerebrovascular diseases are generally exclusionary for the clinical diagnosis. During recent years both epidemiological and neuropathological studies have suggested an association between Alzheimer's disease and several vascular risk factors, such as hypertension, inheritance of the apolipoprotein E epsilon4 allele, coronary heart disease, diabetes mellitus, ischaemic white matter lesions and generalised atherosclerosis. These findings may reflect an overdiagnosis of Alzheimer's disease in individuals with silent cerebrovascular disease or that cerebrovascular disease may affects the clinical expression of Alzheimer's disease. Further possibilities include that Alzheimer's disease may increase the risk of vascular disease or that vascular disease may stimulate the Alzheimer's disease process. Similar mechanisms may also be involved in the pathogenesis of both disorders, such as disturbances in the renin-angiotensin system, apoptosis, and psychological stress.
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PMID:Vascular aspects in Alzheimer's disease. 1096 16

Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE(-/-)) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE(-/-) mice and mice doubly deficient for apoE and PAI-1 (PAI-1(-/-)/apoE(-/-)). Consistent with a previous report, PAI-1(+/+)/apoE(-/-)and PAI-1(-/-)/apoE(-/-) mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow. (Blood. 2000;96:4212-4215)
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PMID:Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. 1111 Jun 93

The present review focuses on evolving concepts in the pathogenesis and management of deep and lobar intracerebral hemorrhage subtypes, with particular focus on the relationship between lobar intracerebral hemorrhage, apolipoprotein E subtypes and cerebral amyloid angiopathy; deep intracerebral hemorrhage and the potential interaction between hypertension and low cholesterol; and new concepts in medical and surgical therapy for acute intracerebral hemorrhage.
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PMID:Intracerebral hemorrhage: update. 1117 25

Analysis of causative mutations and genetic risk factors aid in the understanding of important processes of cerebral amyloid angiopathy (CAA) in humans. We identified a mutation at a novel site of the beta-amyloid precursor protein (AbetaPP) gene associated with familial CAA; this mutation causes an aspartate to asparagine substitution at position 23 of the Abeta peptide. Neuropathological analysis of a 68-year-old man with this mutation showed dramatic Abeta deposition in blood vessels, diffiuse parenchymal Abeta deposits, dystrophic neurites and neurofibrillary tangles. The Abeta deposition showed complete co-localization of Abeta40 and Abeta42, compared to the predominant Abeta42 deposition seen in AD. We hypothesize that the loss of an acidic residue at position 23 of Abeta might be important in the process of Abeta aggregation on smooth muscle cells on the cerebrovasculature. We also analyzed how the apolipoprotein E (APOE) gene might influence aggregation of Abeta by examining the physical association of apoE domains with Abeta via immunohistochemistry. We found that the lipid-binding domain of apoE was more strongly associated with Abeta than the receptor-binding domain, and that 40% of all Abeta deposits had no apoE bound to them. We suggest that the initial deposition of Abeta occurs in the absence of apoE, and that the process of Abeta deposit growth or stabilization is apoE-dependent.
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PMID:The effects of AbetaPP mutations and APOE polymorphisms on cerebral amyloid angiopathy. 1167 89

Determining the effectiveness of candidate treatments for preventing hemorrhagic strokes caused by cerebral amyloid angiopathy will require clinical drug trials. This article explores tvo potential outcome markers for such trials: (1) clinical recurrence of hemorrhagic stroke, and (2) the appearance of small, clinically silent hemorrhagic lesions on gradient-echo MRI. Using pilot data from our cohort of survivors of lobar hemorrhage, we estimated the sample sizes required to demonstrate efficacy with each of these outcome markers as the study endpoint. A study with recurrent hemorrhagic stroke as the endpoint was estimated to require 145 patients per treatment arm to demonstrate a 50% reduction in the recurrence rate over a 24-month follow-up period, while a study using new hemorrhagic lesions on MRI was estimated to require 70 patients per arm for a 17-month follow-up interval. The required sample sizes could be further reduced (to 105 and 52 patients, respectively) by limiting the analysis to those at highest risk of recurrence, defined according to apolipoprotein E genotype or the presence of more than one hemorrhagic lesion at study entry. This analysis suggests that radiographic detection of small hemorrhages may be an efficient surrogate endpoint for pilot trials of promising therapeutic approaches to cerebral amyloid angiopathy.
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PMID:Outcome markers for clinical trials in cerebral amyloid angiopathy. 1167 92

The relationship between cerebral amyloid angiopathy and hemorrhage was investigated by an immunohistochemical study of biopsy cases to characterize the involvement of amyloid beta-protein, apolipoprotein E, and cystatin C in cerebral amyloid angiopathy associated with hemorrhage. The amyloid-laden vessels were examined in biopsy specimens from 41 surgical cases of sporadic cerebral amyloid angiopathy (36 cases with hemorrhage and 5 cases without hemorrhage), using immunohistochemical staining with antibodies against amyloid beta-protein, apolipoprotein E, cystatin C, and alpha-smooth muscle actin. The relationship between the occurrence, recurrence, and enlargement of the hemorrhage, and the semiquantitative estimation of the cerebrovascular amyloid-related protein deposition was analyzed using Fisher's exact test. Severe amyloid beta-protein (p < 0.013) and apolipoprotein E (p < 0.013) immunoreactivity were risk factors for the occurrence of the hemorrhage. Severe cystatin C immunoreactivity was a risk factor for the occurrence (p < 0.002) and enlargement (p < 0.014) of the hemorrhage, and tended to induce recurrent hemorrhage (p < 0.103). In addition, loss of the vascular smooth muscle was observed in the intensely amyloid-laden vascular walls that showed cystatin C-immunoreactivity. The present study indicates that intense amyloid beta-protein deposition with cystatin C deposition weakens the cerebrovascular walls, and that cystatin C deposition is a strong predictor of hemorrhage in cerebral amyloid angiopathy.
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PMID:Cerebral amyloid angiopathy associated with hemorrhage: immunohistochemical study of 41 biopsy cases. 1176 Mar 81

Membrane vesicles (MVs) released from activated cells and blebs from apoptotic cells are increased in patients with vascular disease and in those with atherosclerotic lesions, and their contribution to inflammatory reactions has been suggested. At sites of inflammation, MVs could serve as rapidly available substrates for peroxidation, carry oxidized compounds to activate other cells, and amplify inflammation. Here, we show that MVs released from tert-butyl hydroperoxide-treated endothelial cells (ECs) and apoptotic blebs, but not MVs from Ca(2+) ionophore-treated ECs, stimulate monocyte adhesion to ECs, an important step in atherogenesis. We show that oxidized phospholipids, such as the previously identified 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC), are responsible for biological activity in MVs and apoptotic blebs. Natural antibodies from apolipoprotein E-null mice that recognize POVPC also recognize oxidized MVs, and pretreatment of MVs with these antibodies inhibits their ability to activate ECs. Furthermore, the biological activity of oxidized MVs is inhibited by platelet-activating factor receptor antagonists, which have been shown to inhibit the action of POVPC. Taken together, we show that oxidized MVs and apoptotic blebs stimulate ECs to specifically bind monocytes, with oxidized phospholipids (POVPC) being the active principle. In addition to oxidized lipoproteins, oxidized MVs and apoptotic blebs may play an important role in chronic inflammatory diseases, such as atherosclerosis.
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PMID:Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. 1178 68

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The mechanism underlying this increased risk is not completely clear, yet mounting evidence supports the idea that the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its conformation and clearance plays a major role. Evidence to support this concept comes from in vitro and in vivo studies of apoE/Abeta interactions and the effects of these interactions on Abeta conformation and cellular clearance. Recent studies on the effect of murine and human apoE in APP transgenic mice provide direct evidence that apoE is critically involved in the in vivo converstion of Abeta into forms which contain high 5-sheet content and associated cellular toxicity (neuritic plaques and CAA). These studies also suggest a role for human apoE in Abeta clearance in vivo.
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PMID:Role of apoe/Abeta interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. 1181 88

The aim of this study is to investigate the influence of the E4 allele of apolipoprotein E (apo E) on restenosis after percutaneous transluminal coronary angioplasty (PTCA). The subjects were 171 male patients with more than 75% luminal diameter stenotic lesions of the coronary artery who had undergone an elective initial PTCA. The PTCA was successful in 164 patients, 157 of whom completed a prospective 5 month coronary angiography (CAG) follow up to assess the degree of restenosis after their surgery. Patients with previous coronary artery bypass grafting surgery (CABG), 3 vessel disease, complete obstruction or calcified lesions of the coronary artery, cerebro-vascular disease (CVD), arteriosclerosis obliterans (ASO), and renal failure with hemodialysis were excluded, leaving 105 patients in the analysis. Subjects carrying the E4 allele (n = 22, Phenotype E4/2 = 2, E4/3 = 19, E4/4 = 1: E4 group) were well matched with non-carriers (n = 83, Phenotype E2/2 = 0, E3/2 = 4, E3/3 = 79: E3 group) for clinical, and pre-and post-PTCA angiographic features. The restenosis rates were significantly higher in the E4 group than in the E3 group (patient restenosis rate : 59.1 vs 33.7% p < 0.05, lesion restenosis rate: 51.8 vs 30.9% p < 0.05). These results suggest that the E4 allele is associated with a higher restenosis rate after PTCA.
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PMID:The E4 allele of apolipoprotein E is associated with increased restenosis after coronary angioplasty. 1188 54


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