Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease

Xu, Pu; Li, Yi-Ju; Qin, Xue; Scherzer, Clemens R.; Xu, Hong; Schmechel, Donald E.; Hulette, Christine M.; Ervin, John F.; Gullans, Steven R.; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Gilbert, John R.

doi:10.1016/j.nbd.2005.07.004

Cited by 69 publications

(67 citation statements)

References 74 publications

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“…One possibility is that apoE4 perturbs expression of mitochondrial energy metabolism genes. In a gene expression profiling study of postmortem human hippocampus, apoE4 gene expression was found to be associated with down-regulation of gene transcripts of mitochondrial respiratory complexes I, IV, and V from the nuclear genome, compared with apoE3 (44). In our study, expression of apoE4 in N2A cells reduced the levels of mitochondrial gene transcripts from both the nuclear genome (complex V subunit ␣) and mtDNA (complex IV subunit 1) (Fig.…”

Section: Discussionsupporting

confidence: 55%

Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease

Chen

Dodson

et al. 2011

Journal of Biological Chemistry

161

137

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Apolipoprotein (apo) E4 is the major genetic risk factor for late-onset Alzheimer disease (AD). ApoE4 assumes a pathological conformation through an intramolecular interaction mediated by Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain, referred to as apoE4 domain interaction. Because AD is associated with mitochondrial dysfunction, we examined the effect of apoE4 domain interaction on mitochondrial respiratory function. Steady-state amounts of mitochondrial respiratory complexes were examined in neurons cultured from brain cortices of neuron-specific enolase promoter-driven apoE3 (NSE-apoE3) or apoE4 (NSEapoE4) transgenic mice. All subunits of mitochondrial respiratory complexes assessed were significantly lower in NSEapoE4 neurons compared with NSE-apoE3 neurons. However, no significant differences in levels of mitochondrial complexes were detected between astrocytes expressing different apoE isoforms driven by the glial fibrillary acidic protein promoter, leading to our conclusion that the effect of apoE4 is neuron specific. In neuroblastoma Neuro-2A (N2A) cells, apoE4 expression reduced the levels of mitochondrial respiratory complexes I, IV, and V. Complex IV enzymatic activity was also decreased, lowering mitochondrial respiratory capacity. Mutant apoE4 (apoE4-Thr-61) lacking domain interaction did not induce mitochondrial dysfunction in N2A cells, indicating that the effect is specific to apoE4-expressing cells and dependent on domain interaction. Consistent with this finding, treatment of apoE4-expressing N2A cells with a small molecule that disrupts apoE4 domain interaction restored mitochondrial respiratory complex IV levels. These results suggest that pharmacological intervention with small molecules that disrupt apoE4 domain interaction is a potential therapeutic approach for apoE4-carrying AD subjects. Apolipoprotein (apo)2 E4 is the major genetic risk factor for late-onset Alzheimer disease (AD) (1-6). The protein sequence of apoE4 (299 amino acids) differs from the other two common isoforms (apoE2, apoE3) at residues 112 or 158; apoE3 has a cysteine at residue 112 and an arginine at residue 158, whereas apoE4 has arginines at both positions and apoE2 has cysteines (3, 4). These differences profoundly affect the tertiary protein structure (3-5). ApoE4 displays an intramolecular interaction between its amino-terminal and carboxylterminal domains (7,8), referred to as apoE4 domain interaction. The domain interaction is mediated by Arg-112 in apoE4, which induces a salt bridge between Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain (7,8). This interaction is decreased in apoE2 and apoE3 due to the presence of Cys-112 (8). Substitution of a threonine for Arg-61 in apoE4 disrupts the domain interaction, converting apoE4 to an apoE3-like conformation (7-9).It is postulated that domain interaction is primarily responsible for the pathogenic effects of apoE4 in AD (3-5). Because AD is known to be associated with mitochondrial dysfunction (10 -...

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Section: Discussionsupporting

confidence: 55%

Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease

Chen

Dodson

et al. 2011

Journal of Biological Chemistry

161

137

View full text Add to dashboard Cite

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“…They found the M6a gene was downregulated in the hippocampus of socially and physically stressed animals. In the hippocampus of AD patients, M6a expression has been shown to be down-regulated (46). Here, we have provided compelling evidence that the M6a gene is decreased in the transgenic mouse, therefore, these data support the notion that chronic stress by Tau pathology is related with M6a protein dysfunction and AD progression.…”

Section: Discussionsupporting

confidence: 77%

Characterization of changes in global gene expression in the brain of neuron-specific enolase/human Tau23 transgenic mice in response to overexpression of Tau protein

Woo

Park²,

Kang³

et al. 2010

Int J Mol Med

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Abstract. Tau is a neuronal phosphoprotein responsible for the formation of the neurofibrillary tangles in Alzheimer's disease. To characterize the changes in global gene expression in the brain of transgenic mice that overexpress human Tau23 protein in response to the increase of Tau23 phosphorylation, total RNA extracted from the hippocampus of 12-month-old transgenic and wild-type mice was converted to cDNA, labeled with biotin and hybridized to oligonucleotide microarrays. The microarray results were confirmed by real-time RT-PCR and Western blotting method. It was determined that 43 genes were up-regulated and 8 genes were down-regulated by Tau23 in transgenic mice compared to controls, based on the arbitrary difference in the 2-fold change. Among the up-regulated transcripts, those encoding for transporter and oxidoreductase were dramatically over-represented, followed by those related to regulatory molecule, cytoskeletal protein, signaling molecule, and extracellular matrix protein. Genes encoding for transcription factor, regulatory molecule, miscellaneous function, and chaperone were significantly reduced in the downregulated group. The major genes in the up-regulated categories included Ecrg4, Folr1, Defb11, Aqp1 and Soctdc1. The major genes in the down-regulated categories were Ncor1, Gpm6a, and Hspd1. These results indicate that the microarray analysis identifies several gene functional groups and individual genes that respond to a sustained increase in Tau23 phosphorylation levels in the brain of transgenic mice. In addition, the results suggest the microarray test is a useful tool for increased understanding of the role of Tau23 protein in regulating neurodegenerative disorders.

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“…It is to highlight that recent studies showed that preclinical alterations in brain activation patterns in APOE4 carriers many decades before of the possible dementia onset (at an age of 20-30 years) [38]. In addition, it has been found differences in presence of oxidative stress and expression of synaptic proteins between AD patients with different APOE genotypes [39][40].…”

Section: Apolipoprotein Ementioning

confidence: 96%

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

et al. 2006

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Alzheimer's disease (AD) is one of the main causes of dementia in the world. Increases in life expectancy in the majority of populations around the world have been associated with a higher rate of AD incidence in different countries in past and future decades [1] AD is clinically characterized by cognitive impairment; there is an initial alteration in recent AbstractIn this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.

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Differences in apolipoprotein E3/3 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease

Cited by 69 publications

References 74 publications

Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease

Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease

Characterization of changes in global gene expression in the brain of neuron-specific enolase/human Tau23 transgenic mice in response to overexpression of Tau protein

Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

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