Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.

Strittmatter, Warren J.; Saunders, Ann M.; Goedert, Michel; Weisgraber, Karl H.; Li, Dong; Jakes, Ross; Huang, David; Pericak‐Vance, Margaret A.; Schmechel, Donald E.; Roses, Allen D.

doi:10.1073/pnas.91.23.11183

Cited by 421 publications

(229 citation statements)

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“…However, there is still no consensus regarding the role played by apoE in this, or other, neurodegenerative conditions. Most hypotheses assume that the apoE4 isoform is less effective than the apoE3 isoform in performing a positive function, such as (i) cytoskeletal stability through apoE binding to tau or other microtubule associated proteins (18), and tau phosphorylation (19), (ii) protective effects against neuronal injury through antioxidant activity (20), (iii) neuronal plasticity via effects on neurite outgrowth (21)(22)(23)(24), and (iv) lipid peroxidation (25). ApoE has also been suggested to influence disease pathology via an indirect role through amyloid.…”

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confidence: 99%

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

et al. 2002

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Apolipoprotein E (apoE) has been genetically linked to late-onset Alzheimer's disease (AD). The role of this lipid-transport protein in AD remains to be established. One hypothesis is that apoE, particularly the apoE4 isoform, may have neurotoxic effects as demonstrated using apoE-related synthetic peptides and the N-terminal fragment of apoE. ApoE is a heparan-sulfate binding protein, and apoE peptide neurotoxicity can be blocked by heparin and prevented by degrading heparan sulfate or inhibiting its biosynthesis. The possibility that heparin inhibition of toxicity is mediated by a specific oligosaccharide sequence was investigated using a bioassay to determine the inhibition of apoE peptide toxicity by glycosaminoglycans and purified glycosaminoglycan oligosaccharides. Studies on modified heparins showed that the presence of N-sulfo groups and either 2-or 6-O sulfo groups were required for inhibition of toxicity. Heparin oligosaccharides with eight or more saccharide residues with seven O-sulfo groups and four N-sulfo groups exhibited potent inhibition. Larger oligosaccharides, and heparin and heparan sulfate polymers, afforded comparable, or somewhat better, protective effects but also caused clumping and detachment of cells when administrated alone.Alzheimer's disease (AD) 1 remains the most common form of dementia, with four million Americans currently suffering from it and an estimated 22 million people throughout the world who will be afflicted by 2025. There are no current effective treatments for AD, and the cause of this illness remains unknown despite the tremendous increase in information regarding genetic linkages to the disease. The pathological hallmarks of AD include the accumulation of extracellular plaques containing amyloid and other proteins, the presence of intracellular neurofibrillary tangles, whose effect on neuronal function is not yet known, and the loss of nerve cells and synaptic connections within the areas of the brain responsible for learning and memory. Mutations in three known genes, the amyloid protein precursor and presenilin 1 and 2, nearly always cause the disease (1). These mutations, however, account only for a very small percentage (5-10%) of AD cases. A fourth genetic factor is apolipoprotein E (apoE). Unlike the three other genes, the apoE4 gene is a susceptibility locus accounting for approximately 40-70% of the cases of late-onset AD (2).ApoE is a 299-residue lipid-associated protein that binds and transports cholesterol-rich lipoproteins for internalization via receptors of the low-density lipoprotein (LDL) receptor family (3). In addition, apoE has other putative functions that do not seem to involve lipid transport (4). ApoE plays an important role in maintaining central nervous system functions (4, 5), and recent studies have suggested that apoE is a major risk factor in a number of diseases (6). The N-terminal domain (1-191) is composed of four amphipathic R-helices arranged in an antiparallel fashion and connected by loop regions (7). It contains the lo...

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confidence: 99%

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

et al. 2002

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“…The epsilon 4 allele of the apolipoprotein E (ApoE) gene is associated with Alzheimer's disease (AD), affecting the onset of the disease in an allele dose-dependent manner. 1,2 ApoE4 is associated with increased plaque load in AD [3][4][5] and early onset of neurofibrillary changes. 6 ApoE4 has also been implicated in poor neurological recovery after head injury, cerebral hemorrhage, and cardiac bypass surgery.…”

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confidence: 99%

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Tesseur

Dorpe

Bruynseels

et al. 2000

The American Journal of Pathology

131

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The epsilon 4 allele of the human apolipoprotein E gene (ApoE4) constitutes an important genetic risk factor for Alzheimer's disease. Recent experimental evidence suggests that human ApoE is expressed in neurons, in addition to being synthesized in glial cells. Moreover, brain regions in which neurons express ApoE seem to be most vulnerable to neurofibrillary pathology. The hypothesis that the expression pattern of human ApoE might be important for the pathogenesis of Alzheimer's disease was tested by generating transgenic mice that express human ApoE4 in neurons or in astrocytes of the central nervous system. Transgenic mice expressing human ApoE4 in neurons developed axonal degeneration and gliosis in brain and in spinal cord, resulting in reduced sensorimotor capacities. In these mice, axonal dilatations with accumulation of synaptophysin, neurofilaments, mitochondria, and vesicles were documented, suggesting impairment of axonal transport. In contrast, transgenic mice expressing human ApoE4 in astrocytes remained normal throughout life. These results suggest that expression of human ApoE in neurons of the central nervous system could contribute to impaired axonal transport and axonal degeneration. The epsilon 4 allele of the apolipoprotein E (ApoE) gene is associated with Alzheimer's disease (AD), affecting the onset of the disease in an allele dose-dependent manner. 1,2 ApoE4 is associated with increased plaque load in AD 3-5 and early onset of neurofibrillary changes. 6 ApoE4 has also been implicated in poor neurological recovery after head injury, cerebral hemorrhage, and cardiac bypass surgery. [7][8][9][10][11][12] In addition, ApoE4 was suggested to act as a risk factor for bulbar-onset amyotrophic lateral sclerosis, for Pick's disease, corticobasal degeneration, and progressive supranuclear palsy (characterized by protein Tau-related cytoskeletal pathology), and for inclusion body myositis, although contradictory results have been found. [13][14][15][16][17][18][19] Epidemiological data do not provide evidence for a direct role of ApoE in central nervous system disorders, and its mechanism of action within the central nervous system is not clear. Originally, it was thought that ApoE present in neurons originated only from endocytosis. 20 -22 Numerous cell culture experiments demonstrated receptor-mediated uptake of ApoE as well as effects on neurite outgrowth and cell-morphology. [23][24][25][26][27][28][29] However, more and more evidence indicates that intraneuronal ApoE might also originate from synthesis by neurons. In situ hybridization of brain sections of transgenic mice expressing genomic fragments containing the entire human ApoE locus, including its promoter sequences, revealed expression in neurons, besides astrocytes. 30 -32 Human neuroblastoma cells were shown to synthesize both ApoE mRNA and protein. 33,34 Moreover, in situ hybridization of human brain sections conclusively demonstrated ApoE mRNA in neurons. 35 Taken together these results suggest that besides its well-known synthesis...

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“…99 -101 APOE also interacts with tau in its nonphosphorylated state in vitro in an isoform-specific manner, with the APOE 3 allele binding with a higher affinity to tau than the APOE 4 allele. 102 APOE immunoreactivity has also been localized to SPs and NFTs within the AD brain and other neurodegenerative disorders. 98,103,104 However, the function of APOE in the normal brain as well as its role in the pathogenesis of AD is presently unknown.…”

Section: Apolipoprotein E As a Risk Factor For Admentioning

confidence: 99%

Single cell gene expression profiling in Alzheimer’s disease

et al. 2006

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Summary: Development and implementation of microarray techniques to quantify expression levels of dozens to hundreds to thousands of transcripts simultaneously within select tissue samples from normal control subjects and neurodegenerative diseased brains has enabled scientists to create molecular fingerprints of vulnerable neuronal populations in Alzheimer's disease (AD) and related disorders. A goal is to sample gene expression from homogeneous cell types within a defined region without potential contamination by expression profiles of adjacent neuronal subpopulations and nonneuronal cells. The precise resolution afforded by single cell and population cell RNA analysis in combination with microarrays and real-time quantitative polymerase chain reaction (qPCR)-based analyses allows for relative gene expression level comparisons across cell types under different experimental conditions and disease progression. The ability to analyze single cells is an important distinction from global and regional assessments of mRNA expression and can be applied to optimally prepared tissues from animal models of neurodegeneration as well as postmortem human brain tissues. Gene expression analysis in postmortem AD brain regions including the hippocampal formation and neocortex reveals selectively vulnerable cell types share putative pathogenetic alterations in common classes of transcripts, for example, markers of glutamatergic neurotransmission, synaptic-related markers, protein phosphatases and kinases, and neurotrophins/neurotrophin receptors. Expression profiles of vulnerable regions and neurons may reveal important clues toward the understanding of the molecular pathogenesis of various neurological diseases and aid in identifying rational targets toward pharmacotherapeutic interventions for progressive, late-onset neurodegenerative disorders such as mild cognitive impairment (MCI) and AD.

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Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.

Cited by 421 publications

References 40 publications

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

Inhibition of Apolipoprotein E-Related Neurotoxicity by Glycosaminoglycans and Their Oligosaccharides

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

Single cell gene expression profiling in Alzheimer’s disease

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