Apolipoprotein E in Creutzfeldt-Jacob disease.
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Alleles↗
Biomedical subjects
W J Strittmatter
Publications and source records attributed to W J Strittmatter.
Interaction of apolipoprotein E with laminin increases neuronal adhesion and alters neurite morphology.
The extracellular matrix protein laminin profoundly affects neuronal adhesion, spreading, differentiation, and growth by binding integrin-type cell surface receptors. Laminin binds other basement membrane components, including heparan sulfate proteoglycans. Apolipoprotein E (apoE) also binds basement membrane and heparan sulfate proteoglycans and colocalizes with s-laminin in the neuromuscular junction. We sought to determine whether apoE interacts with laminin and whether, as a result, apoE alters the regulation of neuronal adhesion and differentiation by laminin. We demonstrate high-avidity interaction between apoE and laminin in vitro. Compared to laminin alone, a laminin-apoE substrate produces increased numbers of live, attached hippocampal neurons in culture. In addition, neurons grown on laminin-apoE substrates have larger growth cones, increased neuritic branching, and flattened cell bodies compared to neurons grown on laminin alone. ApoE may be important in the development and maintenance of neurons in the central nervous system by regulating interactions between the neuron and the extracellular matrix.
Apolipoproteins E↗
Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease.
The apolipoprotein E (APOE) epsilon 4 allele carries an increased risk of a patient developing Alzheimer's disease (AD) while the epsilon 2 allele carries a decreased risk. We compared survival from the onset of AD in subjects with different numbers of epsilon 4 alleles and evaluated changes in genotypic frequencies with age. Two subject groups were investigated: unrelated AD case and control subjects, and affected and unaffected members from 74 multiplex AD families. In both subject groups, survival from onset decreased with increasing onset age, was longer in women, and was unrelated to epsilon 4 gene dose. The epsilon 2/epsilon 3 genotype became more common with age (p = 0.004). The epsilon 4 allele decreased in frequency with age in all patient groups but, unexpectedly, remained unchanged in control subjects. We conclude that the progression of AD is not strongly related to epsilon 4 gene dose, that the higher prevalence of AD in women may involve the longer survival of affected women, and that AD and death are competing risks involving APOE that change over time.
Age of Onset↗
Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP2c: implications for Alzheimer's disease.
The apolipoprotein E type 4 allele is a susceptibility gene for late-onset Alzheimer's disease. Apolipoprotein E is found in neurons, some of which contain paired helical filaments made of the microtubule-associated protein tau. Previous studies have demonstrated that the apoE3 isoform, but not the apoE4 isoform, binds tau with high avidity. Because the microtubule-associated protein MAP2c also effects microtubule assembly and stability, we examined interactions between apoE isoforms and MAP2c. Similar to the tau-binding results, apoE3, but not apoE4, bound MAP2c. Binding was detectable down to 10(-9) M MAP2c and 10(-8) M apoE3. Isoform-specific interactions of apoE with the microtubule-associated proteins MAP2c and tau might affect intracellular maintenance of microtubules and could contribute to a time-dependent pathogenesis of Alzheimer's disease.
Alzheimer Disease↗
Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.
The apolipoprotein E (apoE) type 4 allele (APOE4) is a susceptibility gene for late-onset familial and sporadic Alzheimer disease. ApoE is found in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease. Neurofibrillary tangles contain paired helical filaments formed from hyperphosphorylated microtubule-associated protein tau. In vitro, tau binds avidly to apoE3, but not to apoE4, forming a bimolecular complex. Tau phosphorylated with a brain extract does not bind either isoform. ApoE3 binds to the microtubule-binding repeat region of tau, which is also the region that is thought to cause self-assembly into the paired helical filament. Binding studies with fragments of ApoE demonstrate that the tau-binding region of apoE3 corresponds to its receptor-binding domain and is distinct from the region that binds lipoprotein particles or beta/A4 peptide. Isoform-specific interactions of apoE with tau may regulate intraneuronal tau metabolism in Alzheimer disease and alter the rate of formation of paired helical filaments and neurofibrillary tangles.
Alzheimer Disease↗
Alzheimer's disease. Risky apolipoprotein in brain.
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Alzheimer Disease↗
Transthyretin sequesters amyloid beta protein and prevents amyloid formation.
The cardinal pathological features of Alzheimer disease are depositions of aggregated amyloid beta protein (A beta) in the brain and cerebrovasculature. However, the A beta is found in a soluble form in cerebrospinal fluid in healthy individuals and patients with Alzheimer disease. We postulate that sequestration of A beta precludes amyloid formation. Failure to sequester A beta in Alzheimer disease may result in amyloidosis. When we added A beta to cerebrospinal fluid of patients and controls it was rapidly sequestered into stable complexes with transthyretin. Complexes with apolipoprotein E, which has been shown to bind A beta in vitro, were not observed in cerebrospinal fluid. Additional in vitro studies showed that both purified transthyretin and apolipoprotein E prevent amyloid formation.
Amino Acid Sequence↗
Clinical application of apolipoprotein E genotyping to Alzheimer's disease.
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Aged↗
Attenuation of the neurotoxic effect of A beta amyloid peptide by apolipoprotein E.
Alzheimer's disease patients have increased frequency of apolipoprotein E allele c4, suggesting apoE4 is a risk factor determining disease. ApoE binds A beta amyloid peptide with great avidity in vitro and in the neuritic plaque. Potentially, binding of A beta to apolipoprotein E could increase A beta neurotoxicity. However, in hippocampal cultures, 0.1 microM apolipoprotein E eliminated the neurotoxicity of 10 microM A beta. Neuronal rescue was dose-dependent and occurred even after 48 hours exposure to A beta, but was overwhelmed by excess A beta. Thus, interaction between these proteins does not directly increase A beta neurotoxicity, and the role of ApoE in Alzheimer's disease remains to be elucidated.
Amyloid beta-Peptides↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗