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G W Rebeck

Publications and source records attributed to G W Rebeck.

At least 37 records · Page 2Linked to original sources
PubMed2000

Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease.

Beta-amyloid peptide (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease, is derived from the transmembrane beta-amyloid precursor protein (APP) by proteolytic processing. Although mechanisms associated with Abeta generation are not fully understood, it is known that Abeta can be generated within endosomal compartments upon internalization of APP from the cell surface. The low density lipoprotein receptor-related protein (LRP) was previously shown to mediate the endocytosis of APP isoforms containing the Kunitz proteinase inhibitor domain (Kounnas, M. Z., Moir, R. D., Rebeck, G. W., Bush, A. I., Argraves, W. S., Tanzi, R. E., Hyman, B. T., and Strickland, D. K. (1995) Cell 82, 331-340; Knauer, M. F., Orlando, R. A., and Glabe, C. G. (1996) Brain Res. 740, 6-14). The objective of the current study was to test the hypothesis that LRP-mediated internalization of cell surface APP can modulate APP processing and thereby affect Abeta generation. Here, we show that long term culturing of cells in the presence of the LRP-antagonist RAP leads to increased cell surface levels of APP and a significant reduction in Abeta synthesis. Further, restoring LRP function in LRP-deficient cells results in a substantial increase in Abeta production. These findings demonstrate that LRP contributes to Abeta generation and suggest novel pharmacological approaches to reduce Abeta levels based on selective LRP blockade.

Alzheimer Disease↗
PubMed2000

Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease.

OBJECTIVE: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD). DESIGN: A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects. SETTING: The Alzheimer's Disease Research Unit at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, for the initial study (n = 260). For the independent multicenter study (n = 647), an international consortium that included the Massachusetts Alzheimer's Disease Research Center at the Massachusetts General Hospital, Boston; the Scientific Institute for Research and Patient Care, Brescia, Italy; and Alzheimer's research units at the Universities of Basel and Zurich, Switzerland, and Bonn, Goettingen, and Hamburg, Germany. PARTICIPANTS: Five hundred seventeen patients with AD and 390 control subjects. MEASURES: Molecular testing of the KspI polymorphisms in the 5' flanking region and exon 1 of CST3 and the apolipoprotein E (APOE) genotype. Mini-Mental State Examination scores for both patients with AD and control subjects. RESULTS: Homozygosity for haplotype B of CST3 was significantly associated with late-onset AD in both study populations, with an odds ratio of 3.8 (95% confidence interval, 1.56-9.25) in the combined data set; heterozygosity was not associated with an increased risk. The odds ratios for CST3 B/B increased from 2.6 in those younger than 75 years to 8.8 for those aged 75 years and older. The association of CST3 B/B with AD was independent of APOE epsilon4; both genotypes independently reduced disease-free survival. CONCLUSIONS: CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.

Age of Onset↗
PubMed2000

Role of the low-density lipoprotein receptor-related protein in beta-amyloid metabolism and Alzheimer disease.

Deposition of beta-amyloid (A beta), a metabolite of approximately 4 kd of the amyloid precursor protein, is a critical pathological feature in Alzheimer disease. We postulate that deposition reflects an imbalance of A beta synthesis and clearance. Several pathways that impact A beta converge on a single receptor molecule, the low-density lipoprotein receptor-related protein (LRP). This multifunctional receptor is the major neuronal receptor both for apolipoprotein E (apoE, protein; APOE, gene) and for alpha2-macroglobulin (alpha2M, protein; A2M, gene), and it mediates clearance of apoE/A beta and alpha2M/A beta complexes. The LRP also interacts with the amyloid precursor protein itself. In this review, we highlight data that support a role for LRP in A beta metabolism and hypothesize that LRP therefore plays a critical role in Alzheimer disease.

Aged↗
PubMed2000

Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice.

Apolipoprotein E (apoE) has been implicated as a risk factor for Alzheimer's disease and in the deposition, fibrillogenesis, and clearance of the amyloid beta-peptide (Abeta). To examine the in vivo interactions between apoE and Abeta deposition, we examined 12-month-old transgenic (tg) mice expressing human amyloid precursor protein (APP) with the V717F mutation (APP(V717F) homozygous) on an APOE null background. Elimination of APOE resulted in a redistribution and alteration in the character of Abeta deposition in homozygous APP(V717F) tg mice, with a dramatic reduction in cortical and dentate gyrus deposition, prominent increase in diffuse CA1 and CA3 deposition, and prevention of the formation of thioflavin-S-positive deposits. These alterations in Abeta deposition were not mediated by significant changes in regional APP expression, low-density lipoprotein receptor-related protein expression, or soluble Abeta levels. Thus, apoE in APP(V717F) tg mice not only affects the amount and form of Abeta deposition, but also the anatomical distribution of diffuse Abeta deposits. The APP(V717F) tg mouse can serve as a model to investigate genetic influences on the vulnerability of specific neuroanatomical regions to Abeta deposition.

Amyloid beta-Peptides↗
PubMed2000

Plasma beta-amyloid peptide, transforming growth factor-beta 1, and risk for cerebral amyloid angiopathy.

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.

Aged↗
PubMed2000

Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background.

Several lines of evidence implicate apolipoprotein E (apoE) and its receptor--the low density lipoprotein receptor related protein (LRP)--in Alzheimer's disease (AD) pathogenesis, including increased amyloid deposition in human AD brains of people containing the apoE epsilon 4 allele, presence of apoE and LRP in amyloid plaques, and in vitro uptake of amyloid precursor protein (APP) and amyloid beta protein (A beta) by LRP. Studies of crosses of apoE knockout mice with APP transgenic mice support a complex interaction between apoE and A beta deposition. In the Tg2576 mice expressing human APPK670N-M671L, apoE determines the amount, morphology, vascular pattern, and neuropil response to A beta deposits. In the PDAPP mice expressing human APPV717F, apoE also affects the anatomical localization of cerebral A beta deposits. Thus, APP transgenic mice can serve as models to investigate genetic influences on the amount and timing of cerebral amyloidosis, the morphology of amyloid plaques, and the vulnerability of specific neuroanatomical regions to A beta deposition.

Alzheimer Disease↗
PubMed1999

Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease.

Several studies have demonstrated genetic associations between Alzheimer's disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (-219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-epsilon4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the -219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the -219G allele and APOE-epsilon2 and between the -219 T allele and APOE-epsilon4. Controlling for these linkages, we found no independent association between the -219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the -219 polymorphisms.

Alleles↗
PubMed1999

Lack of allelic imbalance in APOE epsilon3/4 brain mRNA expression in Alzheimer's disease.

Although the APOE epsilon4 allele is a strong risk factor for Alzheimer's disease (AD), it is not deterministic, as many APOE epsilon3/4 individuals do not develop AD. It has been hypothesized that this incomplete penetrance is due, in part, to an imbalance of allele expression in heterozygous individuals. In this regard, Lambert et al. (1998) reported that AD individuals have a higher APOE epsilon4/total APOE ratio than non-demented control subjects. We tested this hypothesis using radioactive RT-PCR to quantitate APOE epsilon3 and epsilon4 allele expression levels in AD and non-AD brain samples from APOE epsilon3/4 individuals. Quantitative analyses of amplified products within the linear range of amplification (18-20 cycles) revealed no difference from the expected 1:1 ratio in genomic DNA and in cDNA from AD and control brains. Using high PCR cycle numbers (approximately 30), we observed an artificial elevation of the APOE epsilon3/total APOE ratio in both DNA and cDNA samples, possibly due to DNA heteroduplex formation. Our results do not support the hypothesis that allelic imbalance contributes to the risk of developing AD among APOE epsilon3/4 heterozygote individuals.

Alleles↗
PubMed1999

APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome.

BACKGROUND: Alzheimer disease (AD) neuropathology is present in Down syndrome (DS) after age 35, but dementia onset varies from ages 40 to 70 years. Because of small sample sizes and nonuniform determination of dementia, previous studies produced differing results on the influence of APOE subtypes on AD in DS. OBJECTIVE: To determine the influence of the APOE genotype and gender on development of AD in adults with DS to ascertain similarities with AD in the general population. METHODS: A total of 100 adults with DS (ages 35 to 79 years), almost all of whom were longitudinally assessed by neurologists, underwent APOE genotyping. Dementia onset was determined using criteria applied from the Tenth International Classification of Mental and Behavioral Disorders. This cohort contains the largest number of DS subjects with dementia (n = 57) in a single study, thus increasing reliability of the results. RESULTS: The epsilon2 allele frequency was 4% in those with dementia versus 13% in those without dementia (p = 0.03); epsilon4 allele frequency was 18% in those with dementia versus 13% in those without dementia (p = 0.45). Using APOE-epsilon3/3 as the reference group, the risk ratio for the development of AD at any given time was 0.34 for the APOE-epsilon2/3 group (p = 0.04) and 1.44 for the APOE-epsilon(3/4,4/4) group (p = 0.25). Women were 1.77 times as likely to dement as men at any given point in time (p = 0.04). CONCLUSIONS: The epsilon2 allele confers a protective effect, and women with DS have an increased risk for AD, as in the general population. In this sample, epsilon4 does not confer a significantly increased risk for AD in DS.

Adult↗
PubMed1999

Expression and alternate splicing of apolipoprotein E receptor 2 in brain.

Apolipoprotein E isoforms affect the risk of developing Alzheimer's disease. Apolipoprotein E-associated risk may be related to its binding to and clearance by cell surface receptors, including members of the low-density lipoprotein receptor family. We examined the brain expression of the most recently identified member of this receptor family, apolipoprotein E receptor 2, in human brain and placenta. We analysed apolipoprotein E receptor 2 messenger RNA by reverse transcription-polymerase chain reaction and apolipoprotein E receptor 2 protein by immunohistochemistry. Four exons of the apolipoprotein E receptor 2 message were alternately spliced in both fetal and adult brain tissue. Exon 5, encoding three of the seven ligand binding repeats, was absent in the apolipoprotein E receptor 2 messenger RNA examined. Apolipoprotein E receptor 2 messages lacking exon 8, encoding an epidermal growth factor precursor repeat, exon 15, encoding the O-glycosylation region, or exon 18, encoding a cytoplasmic domain, were also present as minor splice variants in the brain and placenta. No differences were observed in the pattern of apolipoprotein E receptor 2 splicing between control and Alzheimer brains. Immunohistochemistry of mouse brain showed that apolipoprotein E receptor 2 was expressed in neurons throughout the brain, with strong expression in pyramidal neurons of the hippocampus, granule cells of the dentate gyrus, cortical neurons and Purkinje cells of the cerebellum. Thus, apolipoprotein E receptor 2 is the fourth apolipoprotein E receptor identified on neuronal cells.

Alternative Splicing↗
PubMed1999

Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons.

Apolipoprotein E and alpha2-macroglobulin (alpha2M) are genetic risk factors for late-onset Alzheimer's disease, and both bind a cell surface receptor, the low-density lipoprotein receptor-related protein (LRP). To investigate the role of LRP on preventing the accumulation of beta-amyloid peptide (A beta), we examined the effects of alpha2M on the clearance of endogenous A beta. Studies were performed in primary Tg2576 transgenic mouse cortical neuronal cultures expressing human mutant amyloid precursor protein (APP) 695. This system allowed us to follow endogenous A beta using immunoblots to detect monomeric forms of the peptide. A beta and APP levels were measured in conditioned media. We found that activated alpha2M (alpha2M*) substantially decreased soluble A beta levels and had no effect on secreted or full-length APP levels. Native alpha2M, which is not a ligand for LRP, did not affect A beta levels. The receptor-associated protein, which inhibits interaction of all ligands with LRP in vitro, prevented alpha2M*-induced decreases of soluble A beta levels. These data suggest that alpha2M* affects soluble A beta clearance rather than A beta production. Further studies showed that similar A beta clearance via an LRP-mediated pathway was observed after treatment with another LRP ligand, lactoferrin. Taken together, these data demonstrate that alpha2M* enhances the clearance of soluble A beta via LRP in cortical neurons.

Amyloid beta-Peptides↗
PubMed1998

Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.

Recent data have implicated apolipoprotein E (apoE) in neuritic outgrowth, synaptic stability, and Alzheimer's disease; these data led us to examine the normal role of apoE-containing lipoproteins in the central nervous system (CNS). We isolated lipoproteins from human cerebrospinal fluid (CSF) in order to examine their composition and potential functions. CSF particles were composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol. ApoE3 formed homodimers and heterodimers with apoA-II, while apoE4, as expected, was monomeric. We addressed the function of CSF lipoproteins with assays of cholesterol efflux and cholesterol influx. CSF lipoproteins decreased intracellular levels of cholesterol in cholesterol-loaded fibroblasts, suggesting these particles can act to remove excess lipids from cells. CSF lipoproteins competed for 125I-labeled LDL degradation by fibroblasts, suggesting they can also interact with the LDL receptor. Furthermore, CSF lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture. Together, these data support a model of CSF lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage.

Aged↗
PubMed1998

Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease.

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.

Alleles↗
PubMed1998

Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels.

Cerebrovascular deposits of amyloid (cerebral amyloid angiopathy, or CAA) are generally asymptomatic, but in advanced cases, they can lead to vessel rupture and hemorrhage. The process of progression in CAA was studied by comparison of postmortem brains with asymptomatic ("mild") CAA to brains with the form of the disease associated with hemorrhage ("severe CAA"). Cortical and meningeal vessels were immunostained for beta-amyloid and examined by confocal microscopy and by systematic quantitative sampling. We focused on 2 quantitative parameters: the proportion of vessels affected by amyloid (a measure of amyloid seeding of vessels) and the amount of amyloid per affected vessel (a measure of growth of existing lesions). Surprisingly, there was no difference between the proportion of affected cortical vessels in mild and severe CAA (0.29 vs 0.32, p = 0.65), but rather an increase in the area of the 40 amino acid form of beta-amyloid per affected cortical vessel (198.5 +/- 38.7 vs 455.8 +/- 100.9 microm2/vessel, p < 0.007). Increasing doses (from 0 to 1 to 2 copies) of the apolipoprotein E epsilon4 allele were also associated with greater amyloid per vessel without change in the proportion of affected vessels within each class of CAA severity. These findings suggest that progression from asymptomatic to advanced CAA reflects progressive accumulation of amyloid in vessels previously seeded with amyloid, and that this process is selectively enhanced by apolipoprotein E epsilon4.

Aging↗
PubMed1998

Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy.

OBJECTIVE: Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of beta-amyloid in cerebral vessels and specific vasculopathic changes in the amyloid-laden vessels, such as cracking of the vessel wall. Recent reports suggest a positive association between CAA-related hemorrhage and both the apolipoprotein E (APOE) epsilon4 allele and, unexpectedly, the APOE epsilon2 allele. Unlike APOE epsilon4, APOE epsilon2 does not appear to act through increased beta-amyloid deposition. We therefore sought to determine whether it might specifically accelerate the second step in this pathway, that is, development of the vasculopathic changes that lead to hemorrhage. METHODS: To determine the role of APOE in development of vasculopathic changes, we compared APOE genotypes in two groups of postmortem brains: 52 brains with complete amyloid replacement of vessel walls but without vasculopathic changes, and 23 brains with complete amyloid replacement of vessels with the accompanying changes of cracking of the vessel wall and paravascular leaking of blood. RESULTS: Frequency of APOE epsilon2 was significantly greater in the group with vasculopathy (0.09) than the group without (0.01, p = 0.03). The groups did not differ in mean age or extent of neuritic plaques. Analysis of a clinical series of patients with CAA-related hemorrhage confirmed an overrepresentation of APOE epsilon2 as well as an association between this allele and earlier age of first hemorrhage. CONCLUSIONS: These data suggest that APOE epsilon2 and epsilon4 might promote CAA-related hemorrhage through separate mechanisms: epsilon4 by enhancing amyloid deposition and epsilon2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.

Age Factors↗
PubMed1998

Confirmation of an association between a polymorphism in exon 3 of the low-density lipoprotein receptor-related protein gene and Alzheimer's disease.

C766T, a polymorphism in exon 3 of the gene for the low-density lipoprotein receptor-related protein (LRP), was found to be associated with late-onset Alzheimer's disease (AD). We developed a PCR-restriction enzyme-based assay to analyze this allele in 234 AD patients and 103 controls. We confirmed that the LRP C766T polymorphism was in disequilibrium with AD--the C/C genotype was present in 76% of AD patients and 60% of controls (p < 0.01); however, the LRP polymorphism did not influence age at onset of AD.

Adolescent↗
PubMed1997

Lack of association of a polymorphism in the low-density lipoprotein receptor-related protein gene with Alzheimer disease.

BACKGROUND: The apolipoprotein E epsilon 4 (ApoE epsilon 4) allele is associated with an increased risk for development of Alzheimer disease (AD). We hypothesized that polymorphisms in proteins that interact with ApoE also might have an impact on the likelihood of AD developing. We examined a polymorphism in the gene for the low-density lipoprotein receptor-related protein (LRP), because LRP is a major ApoE receptor in the brain that also mediates binding and degradation of secreted Kunitz protease inhibitor forms of amyloid precursor protein. SUBJECTS AND DESIGN: The LRP genotypes in 2 groups were studied. The first group consisted of 130 patients with probable or definite AD (mean +/- SD age, 78.2 +/- 8.9 years) and 64 nondemented, control subjects (mean +/- SD age, 81.7 +/- 12.3 years) who were primarily the spouses of the patients. The second group consisted of individuals from a population-based, epidemiologic study, including 38 cognitively impaired individuals (mean +/- SD age, 79.9 +/- 4.1 years) and 93 nondemented controls (mean +/- SD age, 78.7 +/- 4.4 years). Finally, 22 brains with a neuropathological diagnosis of AD were evaluated for neuronal loss, beta-amyloid deposition, and neurofibrillary tangle number and compared with the LRP genotype. RESULTS: No genetic disequilibrium in LRP allele frequencies between controls and patients with AD or cognitive impairment was observed. No interaction between the ApoE epsilon 4 and LRP genotypes was observed in patients with AD. Moreover, the LRP genotype did not correlate with degree of neuronal loss, beta-amyloid deposition, or neurofibrillary tangle number in individuals examined using quantitative neuropathological techniques. CONCLUSION: This LRP gene polymorphism is not linked with the pathophysiological changes of AD.

Aged↗