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A D Roses

Publications and source records attributed to A D Roses.

At least 55 records · Page 3Linked to original sources
PubMed1999

Sialylated human apolipoprotein E (apoEs) is preferentially associated with neuron-enriched cultures from APOE transgenic mice.

Mice transgenic for human APOE2, E3, and E4 alleles express native 34-kDa human apoE and two sialylated apoE isoproteins with approximate molecular weights of 37 kDa (apoEs) and 39 kDa (apoEs2) in brain. These multiple apoE/apoEs/apoEs2 band patterns on Western blot are also observed in human brain, but are not seen in wild-type mouse brain. Both the 37-kDa apoEs and 39-kDa apoEs2 are coprecipitated with native 34-kDa apoE by antibody to human apoE. Neuraminidase digestion eliminates the 37- and 39-kDa forms and results in a downward shift in the bands to the position of the 34-kDa native form. These sialylated apoE isoproteins are found preferentially associated with neurons and contribute significantly (50-60%) to the total neuronal apoE in neuronal cultures from transgenic mice, while only 5-10% of total apoE is sialylated in cultures enriched in glial cells. In situ hybridization and immunocytochemistry demonstrate apoE mRNA and apoE immunoreactivity are predominantly located in cell soma of neurons, not in neuronal processes.

Animals↗
PubMed1999

Apolipoprotein E expression by neurons surviving excitotoxic stress.

In the adult brain, apolipoprotein E (apoE) mRNA is thought to be expressed by nonneuronal cells. Yet, when a brain damage has occurred, the protein is found in neurons. We have studied apoE expression following systemic kainic acid (KA), injected in rats to induce hippocampal neurodegeneration. We describe two effects. First, a moderate increase of apoE levels in astrocytes. Second, and unexpected, a very strong increase of apoE mRNA levels in clusters of CA1 and CA3 pyramidal neurons. Neuronal identity of these cells is supported by a series of observations. First, apoE hybridization signals were found in cells with morphological characteristics of pyramidal neurons. Second, the cells were positive for the neuronal marker MAP2. Third, the cells were negative for the astrocytic marker GFAP and for the microglia marker OX42. Fourth, the same distribution pattern was found with probes hybridizing to c-fos, a transcription factor transiently expressed in neurons under stress. At 48 and 72 h following KA, most of the excitotoxic cell death had already occurred. Since no morphological signs of programmed cell death were observed in apoE-positive pyramidal neurons, we suggest that expression of apoE by neurons may be part of a rescue program to counteract neurodegeneration.

Animals↗
PubMed1999

No association between the HLA-A2 allele and Alzheimer disease.

The apolipoprotein E (APOE)-4 allele is a major risk factor for late-onset Alzheimer disease (AD), but it does not account for all the genetic variation in late-onset AD; thus, other genetic markers must be examined. Previous studies suggest an HLA-A2 allele association with risk and earlier onset age of AD. Because these effects may be additive to those of APOE-4, we studied HLA-A2 and APOE-4 frequencies in AD patients and cognitively intact controls. A total of 712 unrelated Caucasian subjects included 479 patients with AD (435 sporadic, 44 familial) and 233 controls. Patients (mean+/-SD age 73.9+/-7.9 years, range 42-93 years) had probable AD, according to standard diagnostic criteria; controls (mean+/-SD age 70.4+/-8.5 years, range 37-92 years) were cognitively intact. APOE and HLA-A2 typing used polymerase chain reaction to indicate the number of APOE-4 alleles present as well as the presence (A1/A2, A2/A2 genotypes) or absence (A1/A1 genotype) of HLA-A2. A two-way analysis of variance was used to assess the effect of the HLA-A2 allele on age at onset of dementia. No association between HLA-A2 and APOE-4 was found, and the presence of HLA-A2 allele did not increase AD risk. There was also no evidence for an association between HLA-A2 and earlier onset age of AD. Examination age, sex, family history of AD, and recruitment site had no influence on these results. In conclusion, the HLA-A2 allele did not influence AD risk or onset age in this study population. A2 heterozygosity, and population differences, including stratification sub-structures, and other undetermined factors could contribute to discrepant findings among studies.

Adult↗
PubMed1999

Human apolipoprotein E isoform-specific differences in neuronal sprouting in organotypic hippocampal culture.

The apolipoprotein E (ApoE) epsilon4 allele is a major risk factor for neurodegenerative conditions, including Alzheimer's disease. A role for ApoE is implicated in regeneration of synaptic circuitry after neural injury. In the in vitro mouse organotypic hippocampal slice culture system, we previously showed that cultures derived from ApoE-knockout mice are defective in mossy fiber sprouting into the dentate gyrus molecular layer. This sprouting defect was rescued in cultures from transgenic mice expressing ApoE3 under the control of the human promoter and in ApoE-knockout cultures treated with ApoE3-conditioned media. Although the ApoE3 transgene fully restored sprouting, ApoE4 restored sprouting to only 58% of ApoE3 levels. These data indicate that ApoE isoform-specific effects on neuroregeneration may contribute to its genetic risk for Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Neuropathological features of frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke Family 1684.

Frontotemporal dementia with parkinsonism (FTDP-17) is an autosomal dominant disorder that presents clinically with dementia, extrapyramidal signs, and behavioral disturbances in mid-life and progresses to death within 5 to 10 years. Pathologically, the disorder is characterized by variable neuronal loss and gliosis in the frontal and temporal lobes, limbic structures, and the midbrain. Autopsied individuals from some kindreds display abundant neurofibrillary change while others, including a single affected individual from Duke Family 1684, lack distinctive histological features and exhibit only mild neuronal loss and gliosis in limbic structures and subcortical nuclei when examined by routine silver stain. Recently, mutations in the microtubule associated protein tau have been shown to segregate with the disease in this family and in many other affected kindreds. In order to examine the distribution of tau deposits, we performed tau immunohistochemistry, immunoblotting, and immunoelectron microscopy of tau-containing filaments. Immunohistochemistry revealed numerous tau deposits within glial cells and within neurons. Twisted ribbon-like filaments observed by immunoelectron microscopy were immunodecorated with tau AT8 antibody. Sarkosyl-insoluble tau extracted from the hippocampus and cortex migrated as 2 major bands at 64 and 68 kilodaltons and a minor band at 72 kilodaltons, which after alkaline phosphatase treatment appeared to contain mainly tau isoforms with 4 repeats. Furthermore, the ratio of soluble tau with 4 to 3 microtubule-binding repeats was increased. The role of tau mutations in this disorder is discussed in this paper.

Adult↗
PubMed1999

Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4 allele.

OBJECTIVE: Because subjective memory complaints may indicate subtle functional brain abnormalities, the authors studied the influence of the major genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele, on self-reports of memory performance in middle-aged and older adults. METHOD: Subjective and objective assessments of memory performance were compared in relation to the presence or absence of the APOE-4 allele in 39 cognitively intact persons with mild memory complaints. RESULTS: Subjects with the APOE-4 allele had lower scores on objective verbal memory and on the subjective memory measure for retrospective functioning. Among the subjects in the age range where APOE-4 has its greatest influence on the risk of Alzheimer's disease (55-74 years), the APOE-4 group had lower scores on the subjective memory measure for frequency of forgetting. Moreover, the standardized difference in retrospective functioning scores between the two genetic risk groups increased when the mid-age-range group was examined rather than the whole study group. CONCLUSIONS: The APOE-4 allele is associated with increased subjective memory impairment in middle-aged and older adults. Longitudinal studies of age-related memory loss should include genetic risk and subjective memory measures as potential predictors of decline.

Adult↗
PubMed1998

Apolipoprotein E and Alzheimer's disease. The tip of the susceptibility iceberg.

Apolipoprotein E (APOE) is a true susceptibility polymorphism of the common form of Alzheimer's disease (AD). There are three APOE alleles (epsilon 2, epsilon 3, epsilon 4) that are universally distributed in the population with some variation in allele frequency due to racial and ethnic differences, and are associated with different risks and age of onset distributions. In multiple studies, the positive predictive value for symptomatic possible or probable AD patients who carry at least one epsilon 4 allele was consistently > 95%. Thus, early in the clinical course of dementia, when diagnoses are only 60-70% accurate, the presence of an epsilon 4 allele raises the diagnostic accuracy of AD to 95%. With the anticipation of a second major late-onset AD susceptibility locus on chromosome 12, a matrix of relative susceptibility risks in the population raises many ethical and social questions associated with preclinical prediction. The metabolism of apoE (protein) in the brain is a new and exciting area of neurobiology research made relevant by the association with AD. We have constructed transgenic animals using large human genomic fragments containing human APOE on an APOE-deficit mouse background as well as homologous recombination experiments replacing mouse APOE with human APOE promoter elements. The APOE tissue elements, NOT the human APOE gene coding sequence, is associated with the human pattern of intraneuronal apoE immunoreactivity.

Alleles↗
PubMed1998

Patent income.

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Alzheimer Disease↗
PubMed1998

No association of alpha1-antichymotrypsin flanking region polymorphism and Alzheimer disease risk in early- and late-onset Alzheimer disease patients.

The alpha1-antichymotrypsin (AACT)-155 allele was found elsewhere to have a significant effect on Alzheimer disease (AD) risk in individuals with at least one APOE-4 allele. We compared AACT genotypes of 284 cases of sporadic AD and 172 controls. The frequency of the AACT-155 allele did not differ significantly between cases and controls, either overall or when restricted to subjects with at least one APOE-4 allele. Logistic regression controlling for age and sex failed to show an effect due to AACT either alone or acting with APOE. There was no evidence of an interaction between APOE-4 and the AACT-155 allele to reduce age at onset. Thus, our data do not support an association of AACT-155 with risk or age at onset in AD.

Adult↗
PubMed1998

Regionally specific neuronal expression of human APOE gene in transgenic mice.

Apolipoprotein E (APOE, gene; apoE, protein) is a susceptibility gene for late-onset Alzheimer's disease (AD). To examine whether neurons can synthesize apoE, we performed in situ hybridization on brain tissue of transgenic mice carrying genomic constructs for the three major human APOE alleles. We find human APOE mRNA in glial cells of cerebellum, striatum and cerebral cortex and also in neurons of cerebral cortex, corresponding to apoE localization in humans. Synthesis of apoE by neurons implies that models of AD may need to consider intrinsic apoE production in addition to uptake. Inclusion of human regulatory sequences may result in more realistic transgenic models of human disease.

Alleles↗
PubMed1998

Human apolipoprotein E accelerates microtubule polymerization in vitro.

Apolipoprotein E (apoE) is a 34-kDa protein implicated in Alzheimer's disease (AD) that has recently been identified in neuronal cytoplasm. In cultured neurons, the two major isoforms of apoE (E3 and E4) differentially affect neurite extension, microtubule formation, and the ratio of polymerized to depolymerized tubulin. We therefore examined the effects of apoE3 and apoE4 on microtubule assembly in vitro. ApoE3 and apoE4 equally accelerated microtubule polymerization under conditions of slow microtubule assembly. Controls comprising apolipoprotein A1, bovine serum albumin, trypsin inhibitor, and boiled apoE had no effect, demonstrating specificity of the apoE effect. The ability of both apoE isoforms to accelerate microtubule assembly in vitro suggests that isoform-specific differences in neurite extension may result from differences in the uptake, intracytoplasmic transport, or metabolism of these isoforms.

Animals↗
PubMed1998

Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease.

BACKGROUND: The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain. METHODS: We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS: Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Aged↗