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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)

View Article: PubMed Central - HTML - PubMed

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 The results showed increased APOE-mRNA in LOAD compared to normal (our unpublished data) and validated our published findings obtained using homogenates of brain tissue for the expression analysis...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 In unpublished work, we measured APOE-mRNA levels in whole brains from humanized–APOEe3 and –APOEe4 homozygous mouse models generated by targeted replacement...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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A schematic model describing factors leading to upregulation of ApoE function and the impact on LOAD pathogenesis.
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Figure 3: A schematic model describing factors leading to upregulation of ApoE function and the impact on LOAD pathogenesis.

Mentions: Collectively the studies reviewed here suggest that up-regulated function of APOE due to either enhanced protein activity or increased APOE expression levels may contribute, in part, to the etiology of LOAD. Figure 3 summarizes our proposed model. While this model suggests the triggering event, the biochemical and cell biological pathways that mediate the consequences of this event are still being determined. Our perception of increased APOEe3 protein levels as a LOAD-pathogenic mechanism agrees with the concept that changes in expression levels of ‘normal’ protein in the brain can lead to neurodegenerative diseases. In conclusion, genetic heterogeneity across the APOE-LD region may lead, through different molecular mechanisms, to elevated (‘pathogenic’) ApoE function and possibly explains the extremely strong genetic association of the APOE-LD region with increased LOAD-risk and related phenotypes.


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

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

A schematic model describing factors leading to upregulation of ApoE function and the impact on LOAD pathogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: A schematic model describing factors leading to upregulation of ApoE function and the impact on LOAD pathogenesis.
Mentions: Collectively the studies reviewed here suggest that up-regulated function of APOE due to either enhanced protein activity or increased APOE expression levels may contribute, in part, to the etiology of LOAD. Figure 3 summarizes our proposed model. While this model suggests the triggering event, the biochemical and cell biological pathways that mediate the consequences of this event are still being determined. Our perception of increased APOEe3 protein levels as a LOAD-pathogenic mechanism agrees with the concept that changes in expression levels of ‘normal’ protein in the brain can lead to neurodegenerative diseases. In conclusion, genetic heterogeneity across the APOE-LD region may lead, through different molecular mechanisms, to elevated (‘pathogenic’) ApoE function and possibly explains the extremely strong genetic association of the APOE-LD region with increased LOAD-risk and related phenotypes.

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.


Related in: MedlinePlus