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)

Complex inter-relationships between age-associated illnesses, such as vascular disease and Alzheimer's disease (AD), suggest that biological and genetic pathways may be worthy of examination in centenarian populations to provide insights into human longevity. This is also borne out by the involvement of lipoprotein metabolism and a number of vascular genetic risk factors. Repeated findings of a higher frequency of the apolipoprotein E (APOE) epsilon4 allele in middle-aged subjects compared with centenarians were reported. Furthermore, we have also shown how in different populations there is a significant trend in reduction of serum APOE levels from APOE epsilon2- to epsilon4-carrier as well as significant differences in serum APOE levels respect to age in epsilon4-carriers but only after adjustment for HDL cholesterol. In contrast, findings of increased prevalence of the angiotensin I converting enzyme 1 (ACE1) D allele in French centenarians have not been replicated, suggesting the possibility that regional differences may occur in ACE1(*)D frequency within Europe in centenarians, as has been recently reported for APOE epsilon2 and epsilon4 alleles. A number of studies have examined the potential role in longevity of other genes involved in vascular risk, haemostasis, and blood pressure regulation [methyltetrahydrofolatereductase (MTHFR), apolipoprotein A1 (APOA-I), apolipoprotein C3 (APOC-III), apolipoprotein A4 (APOA-IV), paraoxonase 1 (PON1), plasminogen activator inhibitor type I (PAI-1)], with contrasting results. While further studies are needed to confirm the possible role of APOE concentration as putative longevity factor, this paper provides an overview of genetic vascular factors potentially involved in human longevity.
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PMID:Vascular genetic factors and human longevity. 1501 61

Lacunar brain infarcts and cerebral white matter lesions are frequently observed on magnetic resonance imaging scans in elderly subjects. These lesions are also frequent in patient with cerebral amyloid angiopathy. We examined whether plasma amyloid beta peptide (Abeta) levels are associated with lacunar infarcts and white matter lesions in the general population, and whether the apolipoprotein E (APOE) genotype modifies these associations. We studied 1,077 participants within the population-based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia. Cross-sectional associations were analyzed by regression models with adjustments for age, sex, creatinine levels, and hypertension. In APOE epsilon4 carriers, plasma Abeta levels were positively associated with lacunar infarcts and white matter lesions, whereas in noncarriers no associations were observed. Per standard deviation increase in Abeta(1-40) and Abeta(1-42) levels the odds ratios for lacunar infarcts were 1.72 (95% confidence interval [CI] = 1.22-2.43) and 1.93 (95% CI = 1.31-2.85), the periventricular white matter lesion grade increased by 0.32 (95% CI = 0.08-0.57) and 0.29 (95% CI = 0.00-0.57), and the subcortical white matter lesion volume increased by 0.48 ml (95% CI = 0.04-0.91) and 0.24 ml (95% CI = -0.27-0.75). Higher Abeta levels are associated with more lacunar infarcts and white matter lesions in elderly subjects who carry an APOE epsilon4 allele.
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PMID:Plasma amyloid beta, apolipoprotein E, lacunar infarcts, and white matter lesions. 1504 97

The chimpanzee life span is shorter than that of humans, which is consistent with a faster schedule of aging. We consider aspects of diet that may have selected for genes that allowed the evolution of longer human life spans with slower aging. Diet has changed remarkably during human evolution. All direct human ancestors are believed to have been largely herbivorous. Chimpanzees eat more meat than other great apes, but in captivity are sensitive to hypercholesterolemia and vascular disease. We argue that this dietary shift to increased regular consumption of fatty animal tissues in the course of hominid evolution was mediated by selection for "meat-adaptive" genes. This selection conferred resistance to disease risks associated with meat eating also increased life expectancy. One candidate gene is apolipoprotein E (apoE), with the E3 allele evolved in the genus Homo that reduces the risks for Alzheimer's and vascular disease, as well as influencing inflammation, infection, and neuronal growth. Other evolved genes mediate lipid metabolism and host defense. The timing of the evolution of apoE and other candidates for meat-adaptive genes is discussed in relation to key events in human evolution.
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PMID:Meat-adaptive genes and the evolution of slower aging in humans. 1510 Dec 52

The aims of neurology in Japan in the 21st Century should include establishment of therapeutic measures for neurological diseases, training clinical neurologists to cover both static and dynamic aspects of neurology, and application of gene therapy and neurogenesis to clinical neurology. It is also important to note that once any neurological disease develops, remaining sequelae are usually not curable, so the problem of how to prevent the onset of neurological diseases, that is preventive neurology, will become increasingly important. The key target for prevention in neurology is cerebro-vascular disease, since it is very common. Many risk factors are known for ischemic CVD. However, even for the management of hypertension, the so-called number needed to treat (NNT) is 29-118/5 years for primary prevention and 14-23/5 years for secondary prevention. It is also important to consider genetic factors that influence CVD, including abnormal plasminogen, Lp (a), ACT Isehara 1 gene, apolipoprotein E and so on, since these congenital factors reinforce known acquired risk factors, such as hypertension. In addition, the presence of asymptomatic cerebral infarction, as well as PVH and DSWMH, in MRI T2-weighted images is an important predictor of future symptomatic CVD. Finally, storage of one's own bone marrow cells might be useful, since in the event of onset of CVD, dementia or other neurological diseases, autotransplantation with cytokine might become available for neurogenesis. The results of our recent experiments indicate that this idea may be feasible.
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PMID:[Neurology in the 21st century--the era of preventive neurology utilizing new diagnostic and therapeutic techniques]. 1515 50

The epsilon4 allele of apolipoprotein E APOE is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), and the epsilon2 allele is associated with a decreased risk for AD. There is strong evidence to suggest that a major, if not the main, mechanism underlying the link between apoE and both AD and CAA is related to the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its clearance, aggregation, and conformation. In addition to a number of in vitro studies supporting this concept, in vivo studies with amyloid precursor protein (APP) transgenic mice indicate that apoE and a related molecule, clusterin (also called apolipoprotein J), have profound effects on the onset of Abeta deposition, as well as the local toxicity associated with Abeta deposits both in the brain parenchyma and in cerebral blood vessels. Taken together, these studies suggest that altering the expression of apoE and clusterin in the brain or the interactions between these molecules and Abeta would alter AD pathogenesis and provide new therapeutic avenues for prevention or treatment of CAA and AD.
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PMID:In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. 1518 Dec 53

Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in beta-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5' polymorphism (LRP5') is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with the severity of CAAlep. and CAAcort., implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5'87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition.
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PMID:Genetic-morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy. 1563 27

There is evidence to suggest that certain shared features exist in the pathogenesis of vascular disease and Alzheimer disease (AD) in the general population. In Down syndrome (DS) all adults over the age of 40 years develop sufficient neuropathology for a diagnosis of AD. However, vascular disease is not as common in DS as it is in the general population, particularly with respect to the development of atheromas. We discuss biological mechanisms and risk factors that may be common to both diseases including cholesterol metabolism, inflammation, plasminogen activator inhibitor and apolipoprotein E (Apo E). The study of individuals with DS may help to identify common pathogenic links as well as a disassociation between vascular disease and AD.
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PMID:Alzheimer disease and Down syndrome: factors in pathogenesis. 1563 17

Plasma and serum biochemical markers proposed for Alzheimer disease (AD) are based on pathophysiologic processes such as amyloid plaque formation [amyloid beta-protein (A beta), A beta autoantibodies, platelet amyloid precursor protein (APP) isoforms], inflammation (cytokines), oxidative stress (vitamin E, isoprostanes), lipid metabolism (apolipoprotein E, 24S-hydroxycholesterol), and vascular disease [homocysteine, lipoprotein (a)]. Most proteins or metabolites evaluated in plasma or serum thus far are, at best, biological correlates of AD: levels are statistically different in AD versus controls in some cohorts, but they lack sensitivity or specificity for diagnosis or for tracking response to therapy. Approaches combining panels of existing biomarkers or surveying the range of proteins in plasma (proteomics) show promise for discovering biomarker profiles that are characteristic of AD, yet distinct from nondemented patients or patients with other forms of dementia.
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PMID:Biomarkers of Alzheimer disease in plasma. 1571 23

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Abeta deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Abeta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Abeta species within different brain compartments. These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.
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PMID:Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. 1577 40

The epsilon4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the epsilon2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-beta1-40 peptide (Abeta1-40) with the 22Glu--> Gln "Dutch" mutation caused pericyte death in vitro by a mechanism that involves Abeta fibril-like assembly at the cell surface. It is known that ApoE binds to Abeta and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Abeta-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an epsilon4/epsilon4 genotype were more vulnerable to Abeta than cultures with an epsilon3/epsilon3 or epsilon3/epsilon4 genotype. The one cell culture with the epsilon2/epsilon3 genotype was relatively resistant to Abeta compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Abeta-mediated toxicity of cerebrovascular cells and, in addition, ApoE epsilon2/epsilon3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with epsilon4/epsilon4 cells. Thus, the disparity between ApoE genotype and Abeta-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Abeta cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Abeta and thereby modify Abeta-mediated cell death.
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PMID:Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. 1581 93


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