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G W Rebeck

Publications and source records attributed to G W Rebeck.

At least 19 recordsLinked to original sources
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↗
PubMed1996

Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer's disease.

Our studies of the APOE genotype in AD confirm a strong association of the epsilon 4 allele with development of AD and a decreased risk associated with epsilon 2. From a clinical/neuropathological perspective, the major effects of APOE epsilon 4 are to lower the age of onset and to increase the amount of A beta deposit in the brain. Neither rate of progression nor number of neurofibrillary tangles were affected. We also carried out a longitudinal population-based assessment of the APOE genotype to determine the risk for developing cognitive impairment of someone in the general population based on APOE genotype. APOE epsilon 4 carried about 1.4-fold increased risk, and APOE epsilon 2 about 1.7-fold decreased risk. Thus, inheritance of APOE epsilon 4 is a major biological risk factor for AD, but it has limited utility as a prognostic indicator for development of dementia in an individual.

Age of Onset↗
PubMed1996

Clinical and neuropathological correlates of apolipoprotein E genotype in Alzheimer's disease. Window on molecular epidemiology.

Inheritance of the apolipoprotein E (apo E) epsilon 4 allele has recently been found to be associated with Alzheimer's disease. We have studied the clinical and neuropathological correlates of apolipoprotein E genotype in a large group of Alzheimer's patients. The primary influence on clinical presentation is a shift towards earlier age of onset in individuals who have the apo E epsilon 4 gene: no change in clinical course was observed. In neuropathological studies, we find that the major influence of apo E epsilon 4 is on increased A beta deposition. These results led to a model of the biological interaction between the apo E protein and Alzheimer's disease.

Age of Onset↗
PubMed1996

Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease.

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE epsilon 4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty-one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and A beta deposits were assessed in a high-order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the epsilon 4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. A beta deposition, by contrast, was not related to clinical features but was elevated in association with apoE epsilon 4. These results indicate that apoE epsilon 4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE epsilon 4 on amyloid deposition.

Adult↗
PubMed1996

Lack of association of trinucleotide repeat polymorphisms in very-low-density lipoprotein receptor gene with Alzheimer's disease.

Inheritance of the apolipoprotein E epsilon 4 allele is a risk factor for Alzheimer's disease (AD). A recent report studying Japanese patients suggested that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an apolipoprotein E receptor, the very-low-density lipoprotein receptor, is genetically associated with AD, with overrepresentation of the allele containing five copies of the repeat. We determined the allele frequencies of the very-low-density lipoprotein receptor in 3 white populations totaling 469 individuals. In contrast to the previous report, we found no differences in allele frequencies between case patients and control subjects. The discrepancy could be due to differences in Japanese and white populations. Nonetheless, these data weaken the likelihood that this polymorphism in the very-low-density lipoprotein receptor gene is strongly associated with AD.

Alleles↗
PubMed1996

Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer's disease.

The very low density lipoprotein receptor (VLDL-r) is a cell-surface molecule specialized for the internalization of multiple diverse ligands, including apolipoprotein E (apoE)-containing lipoprotein particles, via clathrin-coated pits. Its structure is similar to the low-density lipoprotein receptor (LDL-r), although the two have substantially different systemic distributions and regulatory pathways. The present work examines the distribution of VLDL-r in the central nervous system (CNS) and in relation to senile plaques in Alzheimer disease (AD). VLDL-r is present on resting and activated microglia, particularly those associated with senile plaques (SPs). VLDL-r immunoreactivity is also found in cortical neurons. Two exons of VLDL-r mRNA are differentially spliced in the mature receptor mRNA. One set of splice forms gives rise to receptors containing (or lacking) an extracellular O-linked glycosylation domain near the transmembrane portion of the molecule. The other set of splice forms appears to be brain-specific, and is responsible for the presence or absence of one of the cysteine-rich repeat regions in the binding region of the molecule. Ratios of the receptor variants generated from these splice forms do not differ substantially across different cortical areas or in AD. We hypothesize that VLDL-r might contribute to metabolism of apoE and apoE/A beta complexes in the brain. Further characterizations of apoE receptors in Alzheimer brain may help lay the groundwork for understanding the role of apoE in the CNS and in the pathophysiology of AD.

Aged↗
PubMed1996

A newly identified polymorphism in the apolipoprotein E enhancer gene region is associated with Alzheimer's disease and strongly with the epsilon 4 allele.

Apolipoprotein E allele 4 (apoE epsilon 4) is a major risk factor for late-onset AD. Inheritance of this allele is associated with an earlier age of onset of dementia in individuals with AD. It is unknown whether other polymorphisms in the apoE gene may influence the effect of apoE epsilon 4 on AD. We screened portions of the promoter enhancer element and of the apoE receptor binding domain for other polymorphisms that could affect risk of AD. In particular, a C/G polymorphism at position +113 of the apoE mRNA in the apoE intron 1 enhancer element (IE1) has been recently identified. We found no other polymorphisms. We studied the relationship of the two alleles of the IE1 polymorphism with AD and found an apparent association between IE1 G and AD (n = 94; p = 0.0515). However, the IE1 G allele is also closely associated with apoE epsilon 4 (p < 0.0001). When the presence of apoE epsilon 4 is covaried, the association between the IE1 G allele and AD is no longer statistically significant (odds ratio = 1.29, 95% confidence interval: 0.44, 3.78). In contrast, epsilon 4 is still highly associated with AD when IE1 G is controlled for (odds ratio = 5.91, 95% confidence interval: 3.29, 10.63). Furthermore, there is no significant association between the age of onset of dementia and the inheritance of the G allele. We believe that the apparent association between IE1 G and AD is a consequence of the association between the epsilon 4 and IE1 G alleles.

Adult↗
PubMed1995

LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation.

The secreted form of beta-amyloid precursor protein (APP) containing the Kunitz proteinase inhibitor (KPI) domain, also called protease nexin II, is internalized and degraded by cells. We show that the low density lipoprotein (LDL) receptor-related protein (LRP) is responsible for the endocytosis of secreted APP. APPs770 degradation is inhibited by an LRP antagonist called the receptor-associated protein (RAP) and by LRP antibodies and is greatly diminished in fibroblasts genetically deficient in LRP. APPs695, which lacks the KPI domain, is a poor LRP ligand. Since LRP also binds apolipoprotein E (apoE)-enriched lipoproteins and inheritance of the epsilon 4 allele of the apoE gene is a risk factor for Alzheimer's disease (AD), these data link in a single metabolic pathway two molecules strongly implicated in the pathophysiology of AD.

Amyloid beta-Protein Precursor↗
PubMed1995

Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

Aged↗
PubMed1995

Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype.

BACKGROUND: The neuropathological changes of Alzheimer's disease occur universally in individuals with Down's syndrome as they reach middle age and worsen with increasing age. Thus, evaluation of patients of various ages with Down's syndrome allows one to construct a life history of the development of neuropathological changes associated with Alzheimer's disease at various points in the disease process. METHODS: We have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and A beta amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with Down's syndrome ranging in age from 4 to 73 years. RESULTS: Neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields, affecting the entorhinal cortex, area CA1/subiculum, then other hippocampal subfields. Although amyloid deposition occurs more evenly in a more widespread distribution, it also accumulates over the years 30 to 50. Surprisingly, examination of the patients available older than 50 years showed no trend toward continued increased deposition of amyloid. Within this group, however, individuals who had inherited the apolipoprotein E (Apo E) epsilon 4 genotype contained more than twice the amyloid burden of individuals who did not inherit the Apo E epsilon 4 genotype. COMMENT: This large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and CA1/subiculum for neurofibrillary tangles and a more widespread but specific topography of A beta deposition. Moreover, it demonstrates quantitatively that the lesions increase to a certain level and then apparently reach a plateau. The level of amyloid deposition in Down's syndrome is higher than in sporadic Alzheimer's disease. Inheritance of the Apo E epsilon 4 genotype appears to be an additional (independent) risk factor for developing higher levels of amyloid accumulation.

Adolescent↗
PubMed1995

Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein.

Both apolipoprotein E and its receptor, the low-density-lipoprotein receptor-related protein (LRP), are associated with senile plaques in Alzheimer's disease. We examined the relationship of other LRP-related molecules to senile plaques. LRP is a multifunctional receptor that binds and rapidly internalizes at least seven ligands: apolipoprotein E, activated alpha 2-macroglobulin, tissue and urokinase-type plasminogen activators, plasminogen activator inhibitor-1, lipoprotein lipase, and lactoferrin. Using immunohistochemistry, we showed that all of these ligands, representing a diverse group of otherwise apparently unrelated proteins, accumulate on senile plaques. We also studied expression of the receptor-associated protein, a physiological inhibitor of LRP, in the hippocampal formation from normal subjects and Alzheimer's disease patients. Receptor-associated protein colocalizes with LRP on neuronal soma, but not on neuronal processes or reactive astrocytes. It is not present on senile plaques. These results suggest that senile plaque-associated LRP can bind its ligands, but clearance of these compounds may be impaired in the vicinity of senile plaques.

Alzheimer Disease↗
PubMed1995

Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype.

Alzheimer's disease (AD) is characterized by formation in brain of neurofibrillary tangles and of amyloid deposits. The major protein component of the former is tau, while the latter are composed of amyloid beta-peptides (A beta), which are derived by proteolytic cleavage of the amyloid beta-protein precursor (APP). Both tau and various secretory APP derivatives including A beta and APPS are present in human cerebrospinal fluid (CSF). To investigate whether clinical signs of AD are paralleled by changes in CSF levels of these proteins, we correlated quantitative measures of dementia severity with CSF concentrations of A beta, of APPS, and of tau. We found that levels of A beta in CSF of AD patients were inversely correlated both to cognitive and to functional measures of dementia severity. In contrast, levels of APPS and of tau did not correlate with dementia severity. Apolipoprotein E (apoE) genotype did not influence CSF levels of A beta, APPS, or tau, which were similar among AD patients with Apo E epsilon 3/3, epsilon 3/4, and epsilon 4/4 alleles. These data indicate that CSF levels of A beta decrease with advancing severity of dementia in AD and suggest that they are independent of a patient's Apo E genotype.

Aged↗