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A M Saunders

Publications and source records attributed to A M Saunders.

At least 109 records · Page 6Linked to original sources
PubMed1994

Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype.

A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-epsilon 3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filaments (PHFs); apoE4 does not bind tau. Tau promotes microtubule assembly and stabilizes microtubules; hyperphosphorylated tau does not bind, thereby destabilizing microtubules. Hyperphosphorylated tau may self-assemble into PHFs. Over time a bias toward destabilization of microtubules and the formation of neurofibrillary tangles may occur in individuals who inherit APOE4 alleles, leading to a shorter functional neuronal life span. This hypothesis focuses attention on two important aspects of AD research design: (1) Although the inheritance of APOE4 is associated with increased risk and decreased age of onset, apoE4 does not directly cause the disease. Our data point to the absence of an important function of apoE3 or apoE2 in individuals who do not inherit these alleles as the genetically relevant metabolic factor. This has important implications for design of experiments directed toward understanding the relevant neuronal metabolism. (2) Should this hypothesis be proven and confirmed, targets for pharmaceutical therapy designed to mimic the metabolic function of apoE3 or apoE2 become a realistic preventive strategy.

Alzheimer Disease↗
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

Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.

Gene dosage of the apolipoprotein E (APOE) epsilon 4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon 2 allele, in addition to the dose effect of the epsilon 4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon 4 alleles, risk of AD is lowest in subjects with the epsilon 2/epsilon 3 genotype, with an additional 23% of AD attributable to the absence of an epsilon 2 allele. The opposite actions of the epsilon 2 and epsilon 4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

Age of Onset↗
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

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↗
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

Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases.

The frequency of the allele for apolipoprotein E type 4 (epsilon 4) is increased in late-onset familial and sporadic Alzheimer's disease (AD). We have examined epsilon 4 frequencies in four distinct, normal, elderly control groups and, most importantly, in patients with amyloid-forming diseases whose epsilon 4 distributions were not previously known (Creutzfeldt-Jakob disease, familial amyloidotic polyneuropathy, Down's syndrome). There were no differences between any of these controls and published control series, cementing the relevance of epsilon 4 for late-onset AD. The increase in late-onset AD was confirmed in two new series.

Age Factors↗
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

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↗
PubMed1993

Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

Aged↗
PubMed1992

Characterization of murine carcinoembryonic antigen gene family members.

The carcinoembryonic antigen (CEA) is a human tumor marker whose gene belongs to a family with more than 20 members. This gene family codes for a group of proteins with in vitro cell adhesion properties and for a group of abundantly expressed pregnancy-specific glycoproteins (PSG) with unknown functions. As a basis for in vivo functional studies, we have started to analyze the murine CEA gene family and have identified five new members (Cea-2 to Cea-6). cDNA clones were isolated for Cea-2, Cea-3, and Cea-6. The deduced amino acid sequences of Cea-2 and Cea-6 indicate three IgV-like (N), followed by one IgC-like (A) domain (N1-N2-N3-A). We have also partially characterized the Cea-2 gene and two additional ones, Cea-4 and Cea-5. Cea-2 and Cea-4 are separated by only 16 kb, suggesting a close linkage of murine CEA-related genes, as found for the human CEA gene family. Cea-5 was located to the proximal region of mouse Chromosome (Chr) 7, which is syntenic to part of human Chr 19, containing the human CEA gene family cluster. Cea-2, Cea-3, and a Cea-4-like gene are differentially transcribed in the placenta during pregnancy, but not in other organs tested. This expression pattern strongly suggests that they represent counterparts of the human PSG subgroup members, despite the presence of multiple IgV-like domains, a feature not found for human PSGs. The more distantly related Cea-5 seems to be ubiquitously expressed. The putative promoter region of Cea-2 lacks typical TATA- or CAAT-boxes, but contains other conserved motifs that could play a role in the initiation of transcription.

Amino Acid Sequence↗
PubMed1991

A proximal mouse chromosome 9 linkage map that further defines linkage groups homologous with segments of human chromosomes 11, 15, and 19.

A 42-cM map of proximal mouse chromosome 9, including eight loci defined by restriction fragment length variants, has been generated. Linkage was established by haplotype analyses of 114 interspecific backcross mice and indicated the following gene order: (centromere) Pvs-5.3 cM-Icam-1/Ldlr-18.4 cM-Thy-1-1.8 cM-Ncam-0.9 cM-Hexa-7.9 cM-Gsta-7.9 cM-Trf. Three of these loci, Pvs, Icam-1, and Hexa, have not been mapped previously. Together with previous mapping studies the current results suggested that chromosomal segments of mouse chromosomes 7 and 9 and chromosomal segments of human chromosomes 11, 15, and 19 derive from a single putative primordial chromosome. The studies support the postulate that detailed analysis of chromosome organization will be useful in defining events in mammalian evolution.

Animals↗