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

The non-amyloid beta component of Alzheimer's disease amyloid (NAC) is detected in cerebral amyloid angiopathy; and the precursor of NAC is now known to be identical to alpha-synuclein (alpha-S), a major component of Lewy bodies in Parkinson's disease. We studied if cerebral vascular cells express alpha-S. Immunohistochemical studies of human cerebral tissues from control and cerebral amyloid angiopathy patients revealed the expression of alpha-S in vascular endothelial and smooth muscle cells. Then we studied the expression of alpha-S in vitro using cultures of vascular cells. Cultures of human umbilical vein endothelial cells and umbilical artery smooth muscle cells were found to constitutively express alpha-S messenger RNA and protein. alpha-S is normally expressed in vascular cells and may play some physiological role in the vascular wall.
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PMID:Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer's disease amyloid, in human cerebral blood vessels. 1205 25

We report a family of Japanese origin that has five individuals from two generations affected by an illness characterized by dementia, a stooped posture and an antiflexion gait with an onset in the fourth or fifth decade of life. Two siblings had a clinical phenotype characterized by dementia and Parkinsonism with stooped posture, rigidity and bradykinesia. Neuropathological alterations in both patients included numerous 'cotton wool' plaques (CWPs), senile plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal rarefaction and gliosis. CWPs were present throughout the cerebral cortex as well as in the caudate nucleus, putamen, claustrum, thalamus, substantia innominata and colliculi. These plaques contained a small quantity of argyrophilic and tau-immunopositive neurites as well as glial fibrillary acidic protein-immunopositive elements. They were mildly fluorescent with thioflavin S and immunopositive using monoclonal antibodies recognizing amyloid beta (A beta) ending at residue 42. The main constituents of CWPs were neuropil elements and extracellular amyloid fibrils. These neuropil elements were small dendrites including spines, axon terminals containing synaptic vesicles and astrocytic processes. Dendrites occasionally contained bundles of paired helical filaments. Dendrites and axons often had an irregular outline and appeared as degenerating osmiophilic processes containing electron-dense mitochondria. Genetic analysis of the proband's affected sibling revealed a novel nucleotide substitution (G to A) in exon 8 of the Presenilin 1 ( PSEN1) gene. This nucleotide change results in a glycine to aspartic acid substitution at residue 217 of the PSEN1 protein. This study provides further evidence of clinical and pathological heterogeneity in dementing illnesses associated with PSEN1 mutations.
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PMID:A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. 1211 59

An insertion (I)/deletion (D) polymorphism in the angiotensin 1-converting enzyme (ACE) gene has, in some studies, been associated with increased risk for Alzheimer's disease (AD), and functionally the enzyme has been implicated in the degradation of amyloid beta protein (Abeta). We have investigated the frequency of the I/D polymorphism in a clinic-based and autopsy-confirmed series of cases of AD, and investigated what impact the I/D polymorphism in ACE gene might have on the extent of Abeta and tau pathology in the frontal cortex in the autopsy-confirmed series. We found no differences in I/D allele or genotype frequencies between the clinic-based and autopsy-confirmed AD cases, or between the pooled clinic-based and autopsy-confirmed AD cases and a series of normal control subjects. Moreover, Abeta (Abeta(40) and Abeta(42)) load, tau load or extent of amyloid angiopathy did not differ between D/D, I/D and I/I genotype groups, though Abeta(42) load tended to be higher in bearers of I/I genotype (compared to D/D genotype). Neither age at onset nor duration of illness differed according to genotype. We conclude therefore that the frequency of ACE I-allele is not increased in AD and, in autopsy-confirmed AD cases, possession of the ACE I allele has no impact upon the pathology of AD, at least in terms of the amount of Abeta or tau deposited in the brain.
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PMID:The angiotensin 1-converting enzyme insertion (I)/deletion (D) polymorphism does not influence the extent of amyloid or tau pathology in patients with sporadic Alzheimer's disease. 1214 33

There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans.
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PMID:Immunization treatment approaches in Alzheimer's and prion diseases. 1216 19

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.
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PMID:Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy. 1238 51

We report serial CT and MRI findings in a biopsy-proven case of cerebral amyloid angiopathy (CAA) with isolated angiitis of the central nervous system (CNS). A 69-year-old man had developed dizziness, dementia, and generalized seizure during the preceding 4 years. An initial examination by brain CT and MRI showed bilateral symmetrical periventricular lesions closely resembling those of Binswanger's disease. Subsequently, the lesions expanded slowly, involving a large area of the right cerebral hemisphere with an obvious mass effect. Since a primary brain tumor was suspected, a brain biopsy was performed, and histopathological examination revealed amyloid beta protein CAA within the meningocortical vessels associated with perivascular monocytic cuffing, indicating the presence of isolated angiitis of the CNS. Multinucleated giant cells containing intracytoplasmic beta protein amyloid around a heavily amyloid-laden cortical vessel were also observed. This is the first case report to show sequential radiographical studies of the leukoencephalopathy associated with CAA and isolated angiitis of the CNS.
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PMID:Serial CT and MRI findings in a patient with isolated angiitis of the central nervous system associated with cerebral amyloid angiopathy. 1255 55

Accumulation of amyloid beta (Abeta) in the extracellular spaces of the cerebral cortex and in blood vessel walls as cerebral amyloid angiopathy is a characteristic of Alzheimer's disease (AD) and the ageing human brain. Studies in animals suggest that Abeta is eliminated from the brain either directly into the blood or along perivascular interstitial fluid drainage channels. The aim of the present study is to define the perivascular route for the drainage of Abeta from the human brain. Smears and paraffin sections of post-mortem cortical tissue from 17 cases of AD and from two controls were stained with thioflavin and for Abeta by immunohistochemistry. Histology and confocal microscopy showed that deposits of Abeta in the cortical parenchyma were continuous with Abeta in capillary walls but Abeta in artery walls was not in continuity with Abeta in brain parenchyma. Quantitative studies supported these observations. The results of this study suggest that when Abeta is eliminated from the extracellular spaces of the human brain by the perivascular route, it enters pericapillary spaces and from there drains along the walls of cortical arteries to leptomeningeal arteries. Factors such as overproduction of Abeta, entrapment of Abeta in drainage pathways and poor drainage of Abeta due to functional changes in ageing arteries might result in the failure of elimination of Abeta from the ageing brain and play a major role in the pathogenesis of AD. Such factors might affect therapies for AD that entail administration of anti-Abeta antibodies to eliminate Abeta from the human brain.
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PMID:Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain. 1266 19

Dysfunction of brain vascular endothelial cells may be associated with the pathogenesis of several diseases including cerebral amyloid angiopathy, hemorrhagic stroke and Alzheimer disease. New model systems are necessary to examine the contribution of brain endothelial cells in these disorders. The Von Willebrand factor gene promoter fragment that spans sequences -487 to +247 targets the expression of LacZ marker gene in transgenic mice specifically to brain vascular endothelial cells. Transgenic mice have been prepared that express human amyloid beta protein precursor protein (AbetaPP) isoforms 695 and 751 (wild-type and Dutch variant mutations) under the regulation of this VWF promoter sequence. These AbetaPP transgenes are specifically expressed in brain vascular endothelial cells. The VWF promoter is a valuable tool for targeting gene expression to brain vascular endothelial cells to provide a model to directly examine endothelial cell placement of genes and their contribution to cerebral vascular disease.
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PMID:Von Willebrand factor promoter targets the expression of amyloid beta protein precursor to brain vascular endothelial cells of transgenic mice. 1271 32

The Dutch, Flemish, Italian, and Arctic mutations in the amyloid precursor protein (APP) gene encode changes within the sequence of the amyloid beta peptide (Abeta) and cause presenile cerebral amyloid angiopathy, cerebral parenchymal amyloidosis, or both. These disorders are caused by accumulation of Abeta, with no evidence of increased Abeta production. Our results showed that these mutations in Abeta make it resistant to proteolytic degradation by neprilysin, the peptidase with the most important role in catabolism of Abeta in the brain. These mutations in Abeta could thus be pathogenic not only by facilitating fibrillogenesis but also by extending the half-life of Abeta in the brain.
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PMID:Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. 1280 42

Vascular dysfunction and inflammatory processes may be early events in the pathology of Alzheimer's disease (AD). Even though amyloid beta-peptides (Abeta) play a prominent role in the initiation and progression of cellular dysfunction in AD, the precise in vivo actions of various Abeta-peptides has not been established. The cerebrovascular actions of the major Abeta-peptides (1-40) and (1-42) in live animals were investigated using an open cranial window technique. We show here that the Abeta-peptides cause vascular lesions, especially in the arterioles. In one set of experiments, leukocytes and platelets were tagged with Rhodamine 6G, soluble Abeta(1-40) infused intravenously for 2 minutes, and the vasculature video recorded for 90 minutes. In a second set of experiments, soluble Abeta(1-40) infusion was followed 30 minutes later by an infusion of soluble Abeta(1-42) and the vasculature recorded for 90 minutes. Fluorescent and transmission electron microscopic examinations demonstrated the following cerebrovascular action of Abeta-peptides: endothelial cell damage, leukocyte adhesion, platelet activation, thrombus formation, impeded blood flow, and smooth muscle cell damage. The vascular disruption observed were similar to those observed in the brains of some AD patients and may represent the initial phase of a vascular inflammatory response associated with cerebral amyloid angiopathy. The combination of Abeta(1-40) and (1-42) produced significantly more vascular disruption than Abeta(1-40) alone. Oral administration of conjugated estrogens in ovariectomized female rats protected them from the deleterious actions of Abeta-peptides. The reported protective effect of estrogen against AD may be mediated in part through prevention of cerebrovascular Abeta toxicity.
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PMID:In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens. 1462 23


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