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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between amyloid beta-protein (A beta) length and the apolipoprotein E (APOE) epsilon 2 allele, which is over-represented in cerebral amyloid angiopathy-related haemorrhage (CAAH), has not previously been examined. Of 57 CAA patients studied, 37 had CAAH. All patients, particularly those with CAAH had more blood vessels immunoreactive for A beta 40 than A beta 42 in both the leptomeninges and cerebral cortex. CAAH patients had more A beta 40-immunoreactive blood vessels in the leptomeninges (p < 0.001) and cortex (p = 0.027) than had non-haemorrhage patients. Cortical blood vessels, the usual source of haemorrhage in CAAH, were more frequently A beta 42 immunoreactive in APOE epsilon 2 carriers than in non-epsilon 2 carriers (p = 0.022). The APOE epsilon 2 allele may predispose to CAAH by increasing the seeding of cortical blood vessels by A beta 42.
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PMID:Amyloid beta-protein length and cerebral amyloid angiopathy-related haemorrhage. 1079 Aug 59

Amyloid beta (A beta) deposits and neurofibrillary pathology are characteristic features of Alzheimer's disease (AD). The association of A beta with cerebral vessels is an intriguing feature of AD. While some degree of cerebral A beta angiopathy involving the leptomeninges and intraparenchymal vessels occurs in almost all cases of AD, the proportion of microvessels within a neocortical region containing deposits of A beta peptide is not known. In this study, we examined a cohort of clinically and pathologically evaluated AD cases to assess the percentage of cerebral microvessels in the temporal cortex and parahippocampal gyrus associated with the predominant, A beta 42 form of the peptide. We also assessed whether the distribution and burden of amyloid was related to apolipoprotein E (APOE) genotype. Using double immunostaining methods, we surprisingly found that at least 40% of the microvessels in the two brain regions contained A beta 42 deposits. There was no correlation of such localization with APOE genotype, however, epsilon 4 homozygotes revealed a greater burden of A beta 40. These observations suggest that high proportions of cortical microvessels are associated with A beta 42, which may affect microvascular function.
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PMID:Distribution of amyloid beta 42 in relation to the cerebral microvasculature in an elderly cohort with Alzheimer's disease. 1081 92

In this brief review, we aim to describe the complex relationship between cerebral amyloid angiopathy (CAA), apolipoprotein E (ApoE), and cerebrovascular lesions in Alzheimer's disease (AD). First, we review the evidence that CAA is associated with, and may cause, specific types of vascular lesions (VLs). In addition to being a leading cause of lobar hemorrhages in the elderly, CAA has been implicated as a likely cause of small infarcts, microinfarcts, and incomplete infarctions in the deep white matter. We also review the role that ApoE4 (the major genetic risk factor for AD) has in predisposing toward CAA, coronary artery disease, and possibly toward cerebrovascular disease. Last, we provide evidence that the association between CAA and VLs is not a spurious one due to an increase in the ApoE4 genotype. Even within patient groups with the same ApoE genotype (specifically, E4/4 homozygotes and E3/3 homozygotes), our recent analyses have found significant increases in VLs in association with severe CAA. We discuss the implications of this finding as advancing a pathogenic role for severe CAA in producing many of the VLs commonly found in AD cases.
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PMID:Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer's disease. 1081 99

Despite the documented association between apolipoprotein E genotype and cerebral amyloid angiopathy (CAA), a substantial proportion of CAA-related hemorrhages occur in patients without known risks for this disorder. Two other factors implicated in the pathogenesis of CAA are the amyloid-beta peptide (preferentially deposited in vessels as a 40-amino acid species) and the multifunctional cytokine transforming growth factor-beta 1 (a specific promoter of vascular amyloid deposition in transgenic models). We measured plasma concentrations of these factors in a series of 25 patients diagnosed with probable or definite CAA-related hemorrhage and compared them with 21 patients with hemorrhage due to probable hypertensive vasculopathy and 42 elderly control subjects without hemorrhage. We found no differences among the groups in concentrations of the 40- or 42-amino acid species of beta-amyloid or either the active or latent form of transforming growth factor-beta 1. While the data do not exclude important roles for these molecules as risks for CAA, they indicate that plasma measurements are not useful in its diagnosis.
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PMID:Plasma beta-amyloid peptide, transforming growth factor-beta 1, and risk for cerebral amyloid angiopathy. 1081

Following the identification of the role of the apolipoprotein E (APOE) gene polymorphism in Alzheimer's disease (AD), this gene was examined in cerebral amyloid angiopathy (CAA). As in AD, the APOE epsilon 4 allele was found to be associated with CAA. Lobar intracerebral hemorrhage is the major clinical manifestation of CAA. Initial studies on a small number of patients with CAA-related hemorrhage (CAAH) identified overrepresentation of APOE epsilon 4. However, it became clear that confounding bias from concomitant AD and the need for pathologically confirmed cases of CAAH would also have to be considered. A larger series of pathologically confirmed cases of CAAH, also assessed for AD pathology, found a surprising overrepresentation of the APOE epsilon 2 allele. Because of the association between CAA and AD, it might have been predicted that patients with CAAH would have a low, rather than a high, epsilon 2 frequency. The overrepresentation of APOE epsilon 2 was present both in patients with and without AD, whereas a high epsilon 4 frequency correlated with concomitant AD. Further studies found that overrepresentation of APOE epsilon 2 is specific for CAAH and is not found in intracranial hemorrhages due to other causes. In CAAH, APOE epsilon 2 may interact with putative risk factors for hemorrhage, including antiplatelet/anticoagulant medication, minor head trauma, and hypertension. Several microvascular abnormalities in amyloid-laden blood vessels have been assumed to antedate CAAH and increase its likelihood. APOE epsilon 2 has now been found to be associated with some of these vascular abnormalities, specifically a "double-barrel" appearance and fibrinoid necrosis. The currently favored interpretation is that APOE epsilon 4 enhances deposition of amyloid-beta protein in the walls of cerebral blood vessels, whereas epsilon 2 is a risk factor for hemorrhage from amyloid-laden blood vessels by promoting specific "CAA-associated vasculopathies."
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PMID:Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage. 1081 5

Amyloid-beta (A beta) deposition in cerebral vessels (cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific A beta protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular, A beta 1-40 carrying the E22Q mutation, as in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), is toxic. We investigated the effects of the A beta-binding protein apolipoprotein E (ApoE) on the toxicity of A beta for cultured human brain pericytes. We compared the toxicity of HCHWA-D A beta 1-40 for pericyte cultures with different ApoE genotypes, studied the accumulation of A beta and ApoE in these different cell cultures, and investigated the effects of exogenous ApoE. Pericyte cultures with an ApoE epsilon 2/epsilon 3 genotype were more resistant to HCHWA-D A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype. Cell death was highest in cultures homozygous for ApoE epsilon 4. The extent to which both A beta ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified ApoE resulted in a decrease in cell death. These data suggest that ApoE4 may direct A beta more efficiently than other ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the ApoE epsilon 4 allele increases the risk of developing Alzheimer's disease, and that the ApoE epsilon 2 allele has a relatively protective effect.
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PMID:Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype. 1081 7

Superoxide, the reduced form of molecular oxygen, has been implicated in the genesis of vascular disease. One potential mechanism involves oxidation of low density lipoprotein into an atherogenic particle. A second involves reaction with nitric oxide to generate peroxynitrite, a highly oxidizing intermediate. A third involves regulation of signal transduction in artery wall cells. One well-characterized pathway for superoxide production resides in macrophages, the cellular hallmark of the early atherosclerotic lesion. Macrophages contain a membrane-bound NADPH oxidase that reduces oxygen to superoxide. In the current studies, we used mice that are deficient in the gp91-phox subunit of the NADPH oxidase-a model of chronic granulomatous disease (CGD)-to explore the role of superoxide in atherosclerotic vascular disease. Wild-type and CGD mice on the C57BL/6 background received a high-fat diet for 20 weeks to induce hypercholesterolemia. At the end of this period, the 2 strains of mice had comparable plasma lipid levels, and their atherosclerotic lesions were similar in size. We also crossed CGD mice with apolipoprotein E-deficient (apoE-/-) mice to generate spontaneously hypercholesterolemic animals that lacked functional NADPH oxidase. After 24 weeks, the CGD-apoE-/- animals had lower plasma cholesterol and triglyceride levels than did the apoE-/- animals, but there was no difference in the extent of atherosclerotic plaque. Our findings suggest that superoxide generated by the NADPH oxidase of phagocytes does not promote atherosclerosis in mice with either diet-induced or genetic forms of hypercholesterolemia.
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PMID:Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. 1084 49

The epsilon4 allele of apolipoprotein E (ApoE) is an important genetic risk factor for Alzheimer's disease (AD). Increasing evidence suggests that this association may be linked to the ability of ApoE to interact with the amyloid-beta (Abeta) peptide and influence its concentration and structure. To determine the effect of ApoE on Abeta and other AD pathology in vivo, we used APPsw transgenic mice and ApoE knockout (-/-) mice to generate APPsw animals that carried two (ApoE +/+), one (ApoE +/-), or no copies (ApoE -/-) of the normal mouse ApoE gene. At 12 months of age, Abeta deposition was present in the cortex and hippocampus and was also prominent within leptomeningeal and cortical blood vessels of all APPsw ApoE +/+ mice. Importantly, although Abeta deposition still occurred in APPsw ApoE -/- mice, no fibrillar Abeta deposits were detected in the brain parenchyma or cerebrovasculature. There was also no neuritic degeneration associated with Abeta deposition in the absence of ApoE. These data demonstrate that ApoE facilitates the formation of both neuritic and cerebrovascular plaques, which are pathological hallmarks of AD and cerebral amyloid angiopathy.
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PMID:Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. 1085 39

Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD.
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PMID:Are cerebrovascular factors involved in Alzheimer's disease? 1086 6

The epsilon 4 allele of apolipoprotein E (APOE denotes gene; apoE denotes protein) is a major risk factor for Alzheimer's disease (AD). More recent evidence indicates an association with a poor outcome after acute brain injury including that due to head trauma and intracerebral hemorrhage. APOE gene polymorphism also influences the risk of hemorrhage in cerebral amyloid angiopathy. These diverse brain disorders seem to have some mechanisms in common. The multiplicity of the roles of apoE within the central nervous system is currently being unraveled. For example, apoE can interact with amyloid beta-protein and tau, proteins central to the pathogenesis of AD. In addition to these effects, it is proposed that one of the major functions of apoE is to mediate neuronal protection, repair and remodeling. In all of the different roles proposed, there are marked apoE-isoform specific differences. Although it remains to be clarified which is the most important mechanism(s) in each disorder in which apoE is involved, these isoform specific differences seem to underly a genetically determined susceptibility to outcome from acute brain injury and to AD with APOE epsilon 4 conferring relative vulnerability. This review focuses on apoE research, from clinical studies to animal models, in AD, acute brain injury and cerebrovascular disease and explores the common mechanisms that may explain some of the complex underlying neurobiology.
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PMID:The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models. 1086 9


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