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The Role of Upregulated APOE in Alzheimer's Disease Etiology.

Gottschalk WK, Mihovilovic M, Roses AD, Chiba-Falek O - J Alzheimers Dis Parkinsonism (2016)

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Affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.

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The first and most firmly established genetic risk factor for sporadic late onset Alzheimer’s disease (LOAD) is the e4 allele of the apolipoprotein E (APOE) gene... Carrying the APOEe4 variant significantly increases the lifetime risk for LOAD, with the number of copies present indicative of level of risk and is associated with lower age of clinical disease onset... However, the molecular mechanism underlying the reported genetic LOAD-associations with APOE LD region in general and APOEe4 haplotype in particular has yet to be discovered... We analyzed the APOE-mRNA counts relative to geometric mean of two housekeeping genes using the nCounter single cell gene expression technology and the nSolver program (NanoString)... The results showed increased APOE-mRNA in LOAD compared to normal (our unpublished data) and validated our published findings obtained using homogenates of brain tissue for the expression analysis... Furthermore, Akram et al. have demonstrated that APOE-mRNA and protein levels in the inferior temporal gyrus and the hippocampus are strongly, positively correlated with the progression of cognitive dysfunction... A recent study showed that endoplasmic reticulum (ER)-mitochondrial communication and mitochondria associated ER membranes (MAM) function-as measured by the synthesis of phospholipids and of cholesteryl esters, respectively-are increased significantly in cells treated with APOEe4-containing astrocyte-conditioned media (ACM) as compared to those treated with APOEe3-containing ACM... APOEe4 and APOEe3 have different lipid-binding characteristics, contributing to greater Aβ-elicited lysosomal leakage and apoptosis in APOEe4-producing cells, and affecting the respective abilities of APOEe3 and APOEe4 to support neuronal maintenance and repair... Interestingly, we showed that SNP rs429358, that defines the APOEe4 haplotype, has a significant effect on APOE-mRNAs levels in temporal cortex obtain from LOAD cases... In unpublished work, we measured APOE-mRNA levels in whole brains from humanized–APOEe3 and –APOEe4 homozygous mouse models generated by targeted replacement... We found that human APOE-mRNA levels are>35% higher in brains of APOEe3 homozygous mice compared to mice homozygotes to APOEe4 (Figure 2)... The analysis of humanized-APOE mice support the findings in LOAD-human brains, suggesting that while the effect of e4 variant is putatively on increased activity of the APOE protein, the effect of the e3 background is possibly executed via regulation of APOE gene expression that determines the steady state amount of the protein.

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The effect of APOE haplotypes on APOE-mRNAs expression levels in human brain tissues from LOAD donorsThe study cohort consisted of brain (temporal and occipital cortex) tissues from Caucasian donors with LOAD. Subjects were genotyped for rs429358 and rs7412 SNPs to determine APOE status. Fold levels of human APOE mRNA were assayed in (A) temporal and (B) occipital tissues by real-time RT-PCR using TaqMan technology and calculated relative the geometric mean of GAPDH- and PPIA-mRNAs reference control using the 2−ΔΔCt method. The expression levels between e3/4 (rs429358-TC) and e3/3 (rs429358-TT) were compared. The values presented here are means levels ± SE adjusted for age, sex, PMI, and Braak and Braak stage.
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Figure 1: The effect of APOE haplotypes on APOE-mRNAs expression levels in human brain tissues from LOAD donorsThe study cohort consisted of brain (temporal and occipital cortex) tissues from Caucasian donors with LOAD. Subjects were genotyped for rs429358 and rs7412 SNPs to determine APOE status. Fold levels of human APOE mRNA were assayed in (A) temporal and (B) occipital tissues by real-time RT-PCR using TaqMan technology and calculated relative the geometric mean of GAPDH- and PPIA-mRNAs reference control using the 2−ΔΔCt method. The expression levels between e3/4 (rs429358-TC) and e3/3 (rs429358-TT) were compared. The values presented here are means levels ± SE adjusted for age, sex, PMI, and Braak and Braak stage.

Mentions: Interestingly, we showed that SNP rs429358, that defines the APOEe4 haplotype, has a significant effect on APOE-mRNAs levels in temporal cortex obtain from LOAD cases. We demonstrated that the level of APOE mRNA was significantly higher in the APOEe3/3 genotype group compared to APOEe3/4-genotype (Figure 1). In unpublished work, we measured APOE-mRNA levels in whole brains from humanized–APOEe3 and –APOEe4 homozygous mouse models generated by targeted replacement [27,28]. We found that human APOE-mRNA levels are>35% higher in brains of APOEe3 homozygous mice compared to mice homozygotes to APOEe4 (Figure 2). The analysis of humanized-APOE mice support the findings in LOAD-human brains, suggesting that while the effect of e4 variant is putatively on increased activity of the APOE protein, the effect of the e3 background is possibly executed via regulation of APOE gene expression that determines the steady state amount of the protein.


The Role of Upregulated APOE in Alzheimer's Disease Etiology.

Gottschalk WK, Mihovilovic M, Roses AD, Chiba-Falek O - J Alzheimers Dis Parkinsonism (2016)

The effect of APOE haplotypes on APOE-mRNAs expression levels in human brain tissues from LOAD donorsThe study cohort consisted of brain (temporal and occipital cortex) tissues from Caucasian donors with LOAD. Subjects were genotyped for rs429358 and rs7412 SNPs to determine APOE status. Fold levels of human APOE mRNA were assayed in (A) temporal and (B) occipital tissues by real-time RT-PCR using TaqMan technology and calculated relative the geometric mean of GAPDH- and PPIA-mRNAs reference control using the 2−ΔΔCt method. The expression levels between e3/4 (rs429358-TC) and e3/3 (rs429358-TT) were compared. The values presented here are means levels ± SE adjusted for age, sex, PMI, and Braak and Braak stage.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836841&req=5

Figure 1: The effect of APOE haplotypes on APOE-mRNAs expression levels in human brain tissues from LOAD donorsThe study cohort consisted of brain (temporal and occipital cortex) tissues from Caucasian donors with LOAD. Subjects were genotyped for rs429358 and rs7412 SNPs to determine APOE status. Fold levels of human APOE mRNA were assayed in (A) temporal and (B) occipital tissues by real-time RT-PCR using TaqMan technology and calculated relative the geometric mean of GAPDH- and PPIA-mRNAs reference control using the 2−ΔΔCt method. The expression levels between e3/4 (rs429358-TC) and e3/3 (rs429358-TT) were compared. The values presented here are means levels ± SE adjusted for age, sex, PMI, and Braak and Braak stage.
Mentions: Interestingly, we showed that SNP rs429358, that defines the APOEe4 haplotype, has a significant effect on APOE-mRNAs levels in temporal cortex obtain from LOAD cases. We demonstrated that the level of APOE mRNA was significantly higher in the APOEe3/3 genotype group compared to APOEe3/4-genotype (Figure 1). In unpublished work, we measured APOE-mRNA levels in whole brains from humanized–APOEe3 and –APOEe4 homozygous mouse models generated by targeted replacement [27,28]. We found that human APOE-mRNA levels are>35% higher in brains of APOEe3 homozygous mice compared to mice homozygotes to APOEe4 (Figure 2). The analysis of humanized-APOE mice support the findings in LOAD-human brains, suggesting that while the effect of e4 variant is putatively on increased activity of the APOE protein, the effect of the e3 background is possibly executed via regulation of APOE gene expression that determines the steady state amount of the protein.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The first and most firmly established genetic risk factor for sporadic late onset Alzheimer’s disease (LOAD) is the e4 allele of the apolipoprotein E (APOE) gene... Carrying the APOEe4 variant significantly increases the lifetime risk for LOAD, with the number of copies present indicative of level of risk and is associated with lower age of clinical disease onset... However, the molecular mechanism underlying the reported genetic LOAD-associations with APOE LD region in general and APOEe4 haplotype in particular has yet to be discovered... We analyzed the APOE-mRNA counts relative to geometric mean of two housekeeping genes using the nCounter single cell gene expression technology and the nSolver program (NanoString)... The results showed increased APOE-mRNA in LOAD compared to normal (our unpublished data) and validated our published findings obtained using homogenates of brain tissue for the expression analysis... Furthermore, Akram et al. have demonstrated that APOE-mRNA and protein levels in the inferior temporal gyrus and the hippocampus are strongly, positively correlated with the progression of cognitive dysfunction... A recent study showed that endoplasmic reticulum (ER)-mitochondrial communication and mitochondria associated ER membranes (MAM) function-as measured by the synthesis of phospholipids and of cholesteryl esters, respectively-are increased significantly in cells treated with APOEe4-containing astrocyte-conditioned media (ACM) as compared to those treated with APOEe3-containing ACM... APOEe4 and APOEe3 have different lipid-binding characteristics, contributing to greater Aβ-elicited lysosomal leakage and apoptosis in APOEe4-producing cells, and affecting the respective abilities of APOEe3 and APOEe4 to support neuronal maintenance and repair... Interestingly, we showed that SNP rs429358, that defines the APOEe4 haplotype, has a significant effect on APOE-mRNAs levels in temporal cortex obtain from LOAD cases... In unpublished work, we measured APOE-mRNA levels in whole brains from humanized–APOEe3 and –APOEe4 homozygous mouse models generated by targeted replacement... We found that human APOE-mRNA levels are>35% higher in brains of APOEe3 homozygous mice compared to mice homozygotes to APOEe4 (Figure 2)... The analysis of humanized-APOE mice support the findings in LOAD-human brains, suggesting that while the effect of e4 variant is putatively on increased activity of the APOE protein, the effect of the e3 background is possibly executed via regulation of APOE gene expression that determines the steady state amount of the protein.

No MeSH data available.