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)

The accumulation of amyloid plaques and amyloid congophilic angiopathy (ACA) in the brains of affected individuals is one of the main pathological features of Alzheimer's disease. Within these deposits, the beta A4 (Ass) polypeptide represents a major component with the C-terminal 39-43 amino acid variants being most abundant. Using a mouse IgG1 MoAb produced by hybridoma beta A4[35-43]-95.2 3B9, which reacts with the epitope is defined by the amino acid residues beta A438[GVV]40, this study has identified a unique conformation within the carboxyl terminus of human beta A4[1-42]. Although the beta A438[GVV]40 sequence is present within the C-termini of human beta A4[1-40] and beta A4[1-43] and the beta A4-containing region of human APP, the beta A4[35-43]-95.2 3B9 MoAb (designated MoAb 3B9) does not bind these polypeptides, demonstrating a high degree of specificity for the beta A438[GVV]40 epitope as presented within the beta A4[1-42] sequence. The beta A4[1-42] epitope bound by MoAb 3B9 is sensitive to heating (100 degrees C for 5 min) and is denatured by SDS but not by oxidative radio-iodination of beta A4 or by adsorption to plastic surfaces or nitrocellulose. The recognition of beta A4 plaque deposits and ACA by MoAb 3B9 within formalin-fixed sections of human AD brain demonstrates the potential of these antibodies for investigating the role of the unique beta A4[1-42] conformation in the development of Alzheimer's disease.
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PMID:Identification of structural variations in the carboxyl terminus of Alzheimer's disease-associated beta A4[1-42] amyloid using a monoclonal antibody. 1142 8

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

Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.
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PMID:Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. 1499 33

Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.
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PMID:A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. 1536 48

BACKGROUND: Anti-Abeta immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Abeta antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.
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PMID:Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. 1558 87

ABCA1 (ATP-binding cassette transporter A1) is a major regulator of cholesterol efflux and high density lipoprotein (HDL) metabolism. Mutations in human ABCA1 cause severe HDL deficiencies characterized by the virtual absence of apoA-I and HDL and prevalent atherosclerosis. Recently, it has been reported that the lack of ABCA1 causes a significant reduction of apoE protein level in the brain of ABCA1 knock-out (ABCA1-/-) mice. ApoE isoforms strongly affect Alzheimer disease (AD) pathology and risk. To determine further the effect of ABCA1 on amyloid deposition, we used APP23 transgenic mice in which the human familial Swedish AD mutant is expressed only in neurons. We demonstrated that the targeted disruption of ABCA1 increases amyloid deposition in APP23 mice, and the effect is manifested by an increased level of Abeta immunoreactivity, as well as thioflavine S-positive plaques in brain parenchyma. We found that the lack of ABCA1 also considerably increased the level of cerebral amyloid angiopathy and exacerbated cerebral amyloid angiopathy-related microhemorrhage in APP23/ABCA1-/- mice. Remarkably, the elevation in parenchymal and vascular amyloid in APP23/ABCA1-/- mice was accompanied by a dramatic decrease in the level of soluble brain apoE, although insoluble apoE was not changed. The elevation of insoluble Abeta fraction in old APP23/ABCA1-/- mice, accompanied by a lack of changes in APP processing and soluble beta-amyloid in young APP23/ABCA1-/- animals, supports the conclusion that the ABCA1 deficiency increases amyloid deposition. These results suggest that ABCA1 plays a role in the pathogenesis of parenchymal and cerebrovascular amyloid pathology and thus may be considered a therapeutic target in AD.
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PMID:Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. 1620 13

A family from the south of Western Australia is described with Dutch cerebral amyloid angiopathy (HCHWA-D). The proband died at age 60 from recurrent lobar haemorrhages in the brain, as did his sister and five other family members. The APP 693 mutation at position 22 of the Abetapeptide resulting in a glutamine for glutamic acid was identified in the proband and the affected sister. Pathologically lobar haemorrhages were found with cerebrovascular angiopathy; neuritic plaques were found but no neurofibrilary tangles. There was a leukoencephalopathy on MRI scanning. Dementia and cognitive decline has not been observed in this family. This is the first family reported outside of Europe and the Northern Hemisphere. The discovery highlights the importance of detecting this rare cause of fatal cerebral haemorrhage as it has implications for gene testing and general medical management.
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PMID:A Western Australian kindred with Dutch cerebral amyloid angiopathy. 1621 28

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.
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PMID:APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. 1638 Jul 21

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.
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PMID:Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. 1661 Oct 10

Accumulation of beta-amyloid protein (Abeta) in the brain is a hallmark of Alzheimer's disease (AD), and Abeta-mediated pathogenesis could result from increased production of Abeta or insufficient Abeta clearance by microglia, astrocytes, or the vascular system. Cell-surface receptors, such as scavenger receptors, might play a critical role in the binding and clearing of Abeta; however, the responsible receptors have yet to be identified. We show that scavenger receptor with C-type lectin (SRCL), a member of the scavenger receptor family containing coiled-coil, collagen-like, and C-type lectin/carbohydrate recognition domains, is expressed in cultured astrocytes and microglia. In contrast to the low expression of SRCL in the wild-type mouse brain, in a double transgenic mouse model of AD (Tg-APP/PS1), immunohistochemistry showed that SRCL was markedly induced in Abeta-positive astrocytes and Abeta-positive vascular/perivascular cells, which are associated closely with cerebral amyloid angiopathy. In patients with AD, the distribution of SRCL was similar to that seen in the Tg-APP/PS1 temporal cortex. The presence of a large number of SRCL/Abeta double-positive particles in the intracellular compartments of reactive astrocytes and vascular/perivascular cells in Tg-APP/PS1 mice and AD patients suggests a role for SRCL in Abeta clearance. Moreover, CHO-K1 cells transfected with SRCL isoforms were found to bind fibrillar Abeta(1-42). These findings suggest that SRCL could be the receptor involved in the binding or clearing of Abeta by glial and vascular/perivascular cells in AD.
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PMID:Possible role of scavenger receptor SRCL in the clearance of amyloid-beta in Alzheimer's disease. 1686 60


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