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

Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-Abeta antibodies to deposited Abeta in brain parenchyma and CAA. Biochemical analyses demonstrated that the 3D6 and 10D5, two N-terminally directed antibodies, bound with high affinity to deposited forms of Abeta, whereas 266, a central domain antibody, lacked affinity for deposited Abeta. To determine whether 266 or 3D6 would exacerbate CAA-associated microhemorrhage, we treated aged PDAPP mice with either antibody for 6 weeks. We observed an increase in both the incidence and severity of CAA-associated microhemorrhage when PDAPP transgenic mice were treated with the N-terminally directed 3D6 antibody, whereas mice treated with 266 were unaffected. These results may have important implications for future immune-based therapeutic strategies for Alzheimer's disease.
 ...
PMID:Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. 1565 99

The importance of cerebral amyloid deposition in the mechanism of neurodegeneration is still debatable. Classic arguments are usually centered on amyloid beta(Abeta) and its role in the neuronal loss characteristic of Alzheimer's disease, the most common form of human cerebral amyloidosis. Two non-Abeta cerebral amyloidoses, familial British and Danish dementias (FBD and FDD), share many aspects of Alzheimer's disease, including the presence of neurofibrillary tangles, parenchymal preamyloid and amyloid deposits, cerebral amyloid angiopathy and a variety of amyloid-associated proteins and inflammatory components. Both early-onset conditions are linked to specific mutations at or near the stop codon of the chromosome 13 gene BRI2 that cause generation of longer-than-normal protein products. Furin-like processing of these longer precursors releases two de novo-created peptides, ABri and ADan, which deposit as amyloid fibrils in FBD and FDD, respectively. Due to the similar pathology generated by completely unrelated amyloid subunits, FBD and FDD, collectively referred to as chromosome 13 dementias, constitute alternative models for studying the role of amyloid deposition in the mechanism of neuronal cell death.
 ...
PMID:Chromosome 13 dementias. 1596 64

Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.
 ...
PMID:Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. 1603 62

Plasma and serum biochemical markers proposed for cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin and predementia syndromes (mild cognitive impairment and other related entities) are based on pathophysiologic processes such as lipoprotein metabolism (total cholesterol, apolipoprotein E, 24S-hydroxy-cholesterol), and vascular disease (homocysteine, lipoprotein(a)); SP formation (amyloid beta(Abeta)-protein, Abeta autoantibodies, platelet APP isoforms), oxidative stress (isoprostanes, vitamin E), and inflammation (cytokines). This review will focus on the current knowledge on circulating serum and plasma biomarkers of cognitive decline and dementia that are linked to cholesterol homeostasis and lipoprotein abnormalities, senile plaque formation and amyloid precursor protein (APP) metabolism, oxidative stress, and inflammatory reactions. Special emphasis will, however, be placed on biomarkers related to lipoprotein metabolism and vascular disease. Analytically, most plasma and serum proteins or metabolites lack reproducibility, sensitivity, or specificity for the diagnosis, risk and progression assessment, or therapeutic monitoring of AD and other dementing disorders. Measures linked to lipoprotein metabolism and vascular disease, APP metabolism, oxidative stress, or inflammation appear altered in AD relative to controls, but lack sufficient discriminatory power. Measures combining several biomarkers or incorporating a range of proteins in plasma and small molecule metabolites are promising approaches for the development of plasma or serum-based diagnostic tests for AD and other dementing disorders, as well as for predementia syndromes.
 ...
PMID:Circulating biomarkers of cognitive decline and dementia. 1613 26

Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.
 ...
PMID:Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. 1620 8

In order to have more specific tools available to approach amyloidogenesis in Alzheimer's disease (AD), we have produced several polyclonal and monoclonal antibodies that recognize specific sequences of the amyloid beta (Abeta) peptide. Here we present results that demonstrate that our monoclonal antibody EM5 recognizes an internal sequence (residues 11-16) of the Abeta peptide. This strategic localization of the epitope allowed us to employ this antibody, together with two previously reported polyclonal antibodies (EM2 and EM3, specific for AbetaX-40 and AbetaX-42, respectively), in an immunohistochemical study aimed at exploring the differential distribution of longer (AbetaX-40/42) and shorter (Abeta17-X) peptides along the various types of amyloid deposits of AD. This antibody panel was used in six AD brains, on sections from associative neocortex, striatum and cerebellar cortex. Single and double immunostaining revealed specific staining of vascular amyloid deposits and neuritic plaques by EM5 antibody, with high co-localization of EM2. Our results suggest that EM5 antibody recognizes pathogenic forms of Abeta deposits (amyloid angiopathy and neuritic plaques) and reveals the existence of a subset of plaques with a profile similar to vascular deposits. Additionally, our results show that diffuse plaques in AD brains may contain Abeta17-X peptides as its principal component. EM5 may be a useful tool in research both on human and transgenic mice tissue that may aid in the study of molecular heterogeneity of plaques in AD.
 ...
PMID:Diversity of senile plaques in Alzheimer's disease as revealed by a new monoclonal antibody that recognizes an internal sequence of the Abeta peptide. 1624 46

It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimer's disease (AD). In the present study, we have investigated the extent of amyloid beta protein (Abeta) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased Abeta40 load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) epsilon4 allele. No differences in total Abeta or Abeta42 load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of Abeta. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE epsilon4 allele, may impair clearance of Abeta, and particularly Abeta40, from the brain across the blood-brain barrier, leading to its 'diversion' into perivascular drainage channels, thereby increasing the severity of CAA in such persons.
 ...
PMID:A 3'-UTR polymorphism in the oxidized LDL receptor 1 gene increases Abeta40 load as cerebral amyloid angiopathy in Alzheimer's disease. 1632 15

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.
 ...
PMID:Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype. 1654 33

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid beta (Abeta) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Abeta peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer's disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Abeta, smooth muscle actin and the carboxyl-terminal peptides to detect Abeta(40) and Abeta(42). While vascular Abeta deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Abeta(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Abeta(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Abeta in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Abeta production and elimination will yield important clues on the pathogenesis of CAA.
 ...
PMID:Differential deposition of amyloid beta peptides in cerebral amyloid angiopathy associated with Alzheimer's disease and vascular dementia. 1655 84

Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to its toxic forms (various forms of Abeta aggregation), and lastly the oxidative, inflammatory, and other effects of toxic Abeta. Fibrillar beta-amyloid peptide, a major component of senile plaques in AD brain, is known to induce microglial-mediated neurotoxicity under certain conditions, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. Abeta-42 oligomers that are soluble and highly neurotoxic, referred to as Abeta-derived diffusible ligands (ADDLs), assemble under conditions that block fibril formation. These oligomers bind to dendrite surfaces in small clusters with ligand-like specificity and are capable of destroying hippocampal neurons at nanomolar concentrations. Evidence is presented that AD is triggered by these soluble, neurotoxic assemblies of Abeta rather than the late stage pathology landmarks of amyloid plaques and tangles. The premise is that AD symptoms stem from aberrant nerve cell signaling and synaptic failure rather than nerve cell death, which nevertheless follows and exacerbates the initial pathologies of AD. The defective clearance of amyloid leads to amyloid angiopathy that in turn perpetuates hypoperfusion that affects formation as well as absorption of CSF thereby altering clearance of amyloid and promoting vascular and parenchymal deposition[1]. Hypoperfusion, the defective clearance of amyloid, and resultant increase in amyloid deposition thus represent a vicious cycle. Chronic vascular hypoperfusion-induced mitochondrial failure results in oxidative damage, which drives caspase 3-mediated Abeta peptide secretion and enhances amyloidogenic APP processing. Intracellular Abeta accumulation in turn promotes a significant oxidative and inflammatory mechanism that generates a vicious cycle of Abeta generation and oxidation, each accelerating the other. Abeta activates astrocytes that add to the oxidative imbalance, upregulate the expression of APP via TGF-beta, and are capable of expressing BACE1. Each of these 3 actions accelerates the larger cycle of cholinergic neuron destruction. As oxidative stress induces lesions of cholinergic nuclei producing a reduction in cholinergic neurotransmission, a subsequent increase in cortical APP involving PKCepsilon leads to accelerated amyloidogenic APP metabolism. The linkage of cholinergic activation and APP metabolism completes an additional feedback loop wherein the damage wrought by Abeta accelerates further Abeta production. A comprehensive vision of the neuropathophysiologic mechanisms that result in AD reveals several vicious cycles within a larger vicious cycle, that is to say, a number of interactive systems that each, once set in motion, amplify their own processes, thus accelerating the development of AD.
 ...
PMID:Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. 1661 Oct 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>