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A D Roses

Publications and source records attributed to A D Roses.

At least 181 records · Page 10Linked to original sources
PubMed1994

Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer's disease and in age-matched controls.

Apolipoprotein E (apoE, protein; APOE, gene) is a susceptibility gene for late-onset familial and sporadic Alzheimer's disease (AD). To examine the role of apoE in the pathogenesis of AD, we used immunocytochemistry to compare apoE localization in the hippocampus of histologically confirmed cases of AD, Parkinson's disease (PD), and normal controls. We confirmed apoE immunoreactivity in astrocytes, senile plaques, blood vessels, and some neurons containing neurofibrillary tangles (NFTs). In addition, we observed apoE immunoreactivity in hippocampal neurons without NFTs in AD and PD patients as well as in some nondemented aged controls. In AD cases, apoE-immunoreactive neurites were closely associated with beta-amyloid (A beta) containing senile plaques and intraneuronal apoE was sometimes associated with immunoreactive tau protein accumulation. Thus, apoE is localized where it may affect the biological expression of two characteristic AD pathological correlates: extracellular A beta deposition and intraneuronal tau metabolism and NFT formation.

Aged↗
PubMed1994

APOE is a major susceptibility gene for Alzheimer's disease.

The initial report on APOE as a susceptibility gene for late-onset Alzheimer's disease was presented a little more than two years ago. During the past year, several significant events have given added impetus to research into Alzheimer's. The association of increased allele frequency of APOE4 with Alzheimer's disease has been reproduced in several dozen laboratories around the world. The protective effect of the APOE2 allele has been reported and also rapidly verified. No evidence exists to support the notion of linkage disequilibrium with any nearby locus on chromosome 19. The neuropathological demonstration of apolipoprotein E (apoE) within neuronal cytoplasm in a location suitable for proposed interaction with microtubule-associated protein tau and MAP2c has introduced a new view of neuronal neurobiology. As apoE is not known to be expressed in neurons, its relationship with cellular receptors, such as the low-density lipoprotein related receptor, and the mechanism of intracellular trafficking are now important research problems. The role of apoE as a metabolic co-factor in neuronal metabolism presents new possibilities for neuronal mechanisms of maintenance and response to stress.

Alzheimer Disease↗
PubMed1994

The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.

Haw River Syndrome (HRS) is a dominant neurodegenerative disease that has affected five generations of an African-American family in rural North Carolina. The disorder represents a unique spectrum of multiple system degenerations resembling Huntington's disease, spinocerebellar atrophy and dentatorubropallidoluysian atrophy (DRPLA), a neurodegenerative disease that has been primarily reported in Japan. Recently, DRPLA has been shown to be due to an expanded trinucleotide repeat located on chromosome 12pter-p12. We have genotyped this family and found HRS to be tightly linked to the DRPLA region. Further examination demonstrates that, despite their distinct cultural origins and clinical and pathological differences, HRS is caused by the same expanded CTG-B37 repeat as DRPLA.

Atrophy↗
PubMed1994

Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study.

To clarify the localization of the glial protein apolipoprotein E (apoE) in human cortical neurons, we employed specific immunoelectron microscopy using a monoclonal antibody to human apoE in surgical specimens of temporal lobe. The specimens were rapidly fixed after excision from five patients undergoing surgery for medically intractable seizures, and postmortem material was also taken from one Alzheimer's disease patient for comparison. Strong apoE immunoreactivity was observed in many astrocytes filling the perinuclear cytoplasm and distal processes completely. Some cortical neurons were also apoE-immunoreactive. ApoE immunoreactivity of neurons was less intense than glial cells and was distributed in a punctate fashion confined to the region of the cell body and proximal dendrites, but not distal processes. These findings suggest that apoE, which is presumably synthesized and stored by astrocytes, may be taken up by cortical neurons in younger adult humans. The presence of apoE in some human neurons may allow apoE to affect neuronal metabolism. Isoform-specific interactions with microtubule-associated proteins, such as tau or MAP2C, could influence the rate of pathology in neurodegenerative diseases such as Alzheimer's disease.

Adult↗
PubMed1994

The role of apolipoprotein E in the nervous system.

Human apolipoprotein (apo)E, an important component of plasma lipoprotein metabolism, was recently linked to Alzheimer's disease. Of the three common apoE alleles, epsilon 4 has emerged as a major risk factor. This review summarizes the data leading to this conclusion and discusses possible mechanisms for apoE involvement based on recent biochemical studies.

Alzheimer Disease↗
PubMed1994

Complex genetic disease: can genetic strategies in Alzheimer's disease and new genetic mechanisms be applied to epilepsy?

Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of late-onset Alzheimer's disease. The role of apolipoprotein E in late-onset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease.

Alleles↗
PubMed1994

Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3.

Late-onset and sporadic Alzheimer's disease are associated with the apolipoprotein E (apoE) type 4 allele expressing the protein isoform apoE4. Apolipoprotein E binds avidly to beta amyloid (A beta) peptide, a major component of senile plaque of Alzheimer's disease, in an isoform-specific manner. The apoE4 isoform binds to A beta peptide more rapidly than apoE3. We observed that soluble SDS-stable complexes of apoE3 or apoE4, formed by coincubation with A beta peptide, precipitated after several days of incubation at 37 degrees C with apoE4 complexes precipitating more rapidly than apoE3 complexes. A beta(1-28) and A beta(1-40) peptides were incubated in the presence or absence of apoE3, apoE4, or bovine serum albumin for 4 d at 37 degrees C (pH 7.3). Negative stain electron microscopy revealed that the A beta peptide alone self-assembled into twisted ribbons containing two or three strands but occasionally into multistranded sheets. The apoE/A beta coincubates yielded monofibrils 7 nm in diameter. ApoE4/A beta coincubates yielded a denser matrix of monofibrils than apoE3/A beta coincubates. Unlike purely monofibrillar apoE4/A beta coincubates, apoE3/A beta coincubates also contained double- and triple-stranded structures. Both apoE isoforms were shown by immunogold labeling to be uniformly distributed along the A beta peptide monofibrils. Monofibrils appeared earlier in apoE4/A beta than in apoE3/A beta in time-course experiments. Thus apoE3 and apoE4 each interact with beta amyloid peptide to form novel monofibrillar structures, apoE4 more avidly, a finding consistent with the biochemical and genetic association between apoE4 and Alzheimer's disease.

Alzheimer Disease↗
PubMed1993

Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations.

Amyloid fibrils were isolated from the brain tissue of two individuals who died with familial Alzheimer's disease, one with the phenylalanine 717 mutation in amyloid precursor protein (APP) and one with the isoleucine 717 APP mutation. After solubilization in guanidine hydrochloride and fractionation by sieve chromatography, low molecular weight fractions were treated with cyanogen bromide to generate the beta-peptide fragment starting after the methionine at position 35. Amino acid sequence analysis of all resultant peptides identified the peptide Val-Gly-Gly-Val-Val-Ile-Ala which represents residues 36-42 of the beta-amyloid peptide. No sequence beyond position 42 was found. These findings show that the amino acid substitution at position 717 is not incorporated into the amyloid deposits and suggests that the mutation may have metabolic affects which determine pathogenesis.

Alzheimer Disease↗
PubMed1993

Expression of alpha-3, alpha-5, and beta-4 neuronal acetylcholine receptor subunit transcripts in normal and myasthenia gravis thymus. Identification of thymocytes expressing the alpha-3 transcripts.

We used amplification of reverse transcribed RNA to investigate the thymic transcription of genes encoding for subunits of neuronal acetylcholine receptors (AcChR). All thymic tissues investigated, which include normal thymi, myasthenic hypertrophic thymi, and both myasthenic and nonmyasthenic thymomas, express transcripts encoding for the alpha-3, the alpha-5, and the beta-4 subunits of AcChR. The thymic transcription of at least three different genes encoding for neuronal AcChR subunits suggests there is expression of neuronal AcChR in thymus. Amplification of reverse transcribed RNA and Northern blotting of thymic and peripheral immunocytes showed that thymocytes but not peripheral lymphocytes express alpha-3 AcChR subunit transcripts. This finding suggests that within the T cell lineage there is transcriptional regulation of the alpha-3 AcChR gene.

Base Sequence↗
PubMed1993

Splicing of an anti-sense Alu sequence generates a coding sequence variant for the alpha-3 subunit of a neuronal acetylcholine receptor.

In this report we demonstrate that an alpha-3 acetylcholine receptor subunit transcriptional variant originates through alternative splicing of a complementary sequence of the right arm of an Alu element. This element is located within the 5.1 Kb intron found between exons 5 and 6 of the alpha-3 acetylcholine receptor subunit gene. The transcriptional variant originates from the normal splicing process and carries an in-frame stop codon. If translated, it should encode for a peptide lacking the 4th transmembrane domain of the normal subunit.

Alternative Splicing↗
PubMed1993

Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.

Amyloid beta-peptide (A beta) deposition in senile plaques and cerebral vessels is a neuropathological feature of Alzheimer disease (AD). We examined the possibility that commonly observed variability in A beta deposition in late-onset AD might be related to apolipoprotein E genotype (APOE gene; the two most common alleles are 3 and 4), since APOE4 is a susceptibility gene for late-onset AD and apolipoprotein E interacts strongly with A beta in vitro. In an autopsy series of brains of late-onset AD patients, we found a strong association of APOE4 allele with increased vascular and plaque A beta deposits. Late-onset AD patients with one or two APOE4 alleles have a distinct neuropathological phenotype compared with patients homozygous for APOE3.

Aged↗
PubMed1993

Sequestration of amyloid beta-peptide.

Amyloid beta-protein, or beta/A4, is a 4-kilodalton peptide that forms poorly soluble extracellular depositions of amyloid in brains and leptomeninges of patients with Alzheimer's disease (AD), Down's syndrome (DS), and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). beta/A4 peptide is a derivative of a large transmembrane glycoprotein (APP) and is found in the extracellular space, i.e., in the cerebrospinal fluid and serum of individuals with and without AD and in the conditioned media of many different cells grown in culture. The mechanism by which normally produced amyloid beta peptide forms extracellular aggregates in patients is unknown. One possible explanation is a failure of a mechanism for removal of the beta/A4 peptide that prevents this highly aggregating peptide from forming extracellular amyloid depositions.

Alzheimer Disease↗
PubMed1993

Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.

Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer disease. Late-onset familial and sporadic Alzheimer disease patients have an increased frequency of one of the three common apoE alleles, epsilon 4, suggesting apoE4 is associated with increased susceptibility to disease. To follow up on this suggestion, we compared the binding of synthetic amyloid beta (beta/A4) peptide to purified apoE4 and apoE3, the most common isoform. Both isoforms bound synthetic beta/A4 peptide, the primary constituent of the plaque and angiopathy, forming a complex that resisted dissociation by boiling in SDS. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer, reduced in nitrogen-purged buffer, and prevented by reduction with dithiothreitol or 2-mercaptoethanol. Binding of beta/A4 peptide was saturable at 10(-4) M peptide and required residues 12-28. Examination of apoE fragments revealed that residues 244-272 are critical for complex formation. Both oxidized apoE4 and apoE3 bound beta/A4 peptide; however, binding to apoE4 was observed in minutes, whereas binding to apoE3 required hours. In addition, apoE4 did not bind beta/A4 peptide at pH < 6.6, whereas apoE3 bound beta/A4 peptide from pH 7.6 to 4.6. Together these results indicate differences in the two isoforms in complexing with the beta/A4 peptide. Binding of beta/A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or beta/A4 peptide, and isoform-specific differences in apoE binding or oxidation may be involved in the pathogenesis of the intra- and extracellular lesions of Alzheimer disease.

Aged↗
PubMed1993

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

Aged↗
PubMed1993

Nicotinic neuronal acetylcholine receptor alpha-3 subunit transcription in normal and myasthenic thymus.

Thymic transcription of the alpha-3 subunit of the AChR was studied through sequencing and PCR analysis of thymic cDNA clones, Northern blotting, and ribonuclease protection assays. This analysis revealed at least three, 3' end sequence variants for the alpha-3 subunit as well as a variant that results from the alternative splicing of an antisense 122 bp Alu sequence between exons 5 and 6 of the normal transcript. The spliced Alu sequence not only shifts the exon 6 reading frame but also carries an in-frame stop codon. If translated, this variant transcript would produce a truncated peptide lacking the fourth transmembrane domain of the subunit and carrying a carboxy terminus dodecapeptide not found in any other known AChR subunit sequence. The putative variant subunit may lack biological activity and should differ antigenically from its normal counterpart. In comparing the normal, the MG hypertrophic, and the MG thymoma for transcription of the alpha-3 subunit and its 122 bp variant, it was found that there were no qualitative or quantitative changes in alpha-3 transcript expression in the MG hypertrophic thymi. Thymomas, however, showed an overall decrease in alpha-3 transcription and a comparative increase in beta-amyloid precursor transcription. The decrease in the levels of alpha-3 transcription in thymomas may be related to the proliferation of thymic epithelial cells.

Amyloid beta-Protein Precursor↗
PubMed1993

Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.

Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.

Alleles↗