Association of ApoE and LRP mRNA levels with dementia and AD neuropathology

Akram, Afia Muhammad; Schmeidler, James; Katsel, Pavel; Hof, Patrick R.; Haroutunian, Vahram

doi:10.1016/j.neurobiolaging.2011.04.010

Cited by 34 publications

(19 citation statements)

References 117 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such an effect is usually carried out by the gene's products including RNA and protein and can be explained by a change in either their qualities (structure or function) or quantity (expression levels) that leads to physiological changes. Differential expression of APOE's RNA and protein have been observed in AD, but APOE RNA levels do not always correlate with ApoE protein levels, and it is unclear whether AD subjects have elevated or decreased APOE expression [31][32][33][34][35][36][37][38].The aim of this study was to revisit APOE's transcriptional pathway, define the APOE CGI's role in this pathway, and determine how the relationship between APOE transcription and the APOE CGI correlates with the risk of AD.…”

Section: Discussionmentioning

confidence: 99%

Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease

et al. 2020

View full text Add to dashboard Cite

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3'-exon, and this CGI's effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.

show abstract

Section: Discussionmentioning

confidence: 99%

Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease

et al. 2020

View full text Add to dashboard Cite

show abstract

“…For example, Zarow et al report increased APOE mRNA levels in the hippocampus of AD cases compared to controls[24] and Matsui et al report increased APOE mRNA levels in temporal cortex of AD donors compared to controls[25]. Furthermore, Akram et al have recently 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[26]. …”

Section: Discussionmentioning

confidence: 99%

The cis‐regulatory effect of an Alzheimer's disease‐associated poly‐T locus on expression of TOMM40 and apolipoprotein E genes

Linnertz

Anderson

Gottschalk

et al. 2014

Alzheimer's & Dementia

View full text Add to dashboard Cite

Introduction We investigated the TOMM40-APOE genomic region that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine if a highly polymorphic, intronic polyT within this region (rs10524523, hereafter 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified: short-S, long-L, very long-VL based on the number of T-residues. Methods We evaluated differences in APOE-mRNA and TOMM40-mRNA levels as a function of 523 genotype in two brain regions from APOEε3/3 Caucasian autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. Results The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40-mRNA levels were higher in VL-homozygotes compared to S-homozygotes in temporal and occipital cortexes from Normal and LOAD subjects. Results of a luciferase reporter system were consistent with the human brain mRNA analysis: the 523-VL polyT resulted in significantly higher expression than the S-polyT. While the effect of polyT length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523-polyT. Conclusions These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.

show abstract

“…Interestingly these plaques are decorated with several inflammatory factors and proteins involved in transport, including ACT, ApoJ, ApoE, and complement factors (Veerhuis et al, 2005;Zhan et al, 1995). Not only is the expression of these proteins locally upregulated in AD affected brain areas (Abraham et al, 1990;Akram et al, 2012;Lidstrom et al, 1998;Veerhuis et al, 2005;Yasojima et al, 1999), these AAPs also play an important role in the dynamic balance between Ab production and removal (Bales et al, 1997;Botto et al, 1997;DeMattos et al, 2002;Mucke et al, 2000), that may ultimately lead to amyloid plaque formation. Indeed, in this study we observed the ability of ACT, ApoJ, ApoE, and SAP-C1q to significantly hamper Ab-uptake by microglia and astrocytes in an Ab-aggregation state depending way.…”

Section: Discussionmentioning

confidence: 99%

Apolipoproteins E and J interfere with amyloid‐beta uptake by primary human astrocytes and microglia in vitro

Mulder

Nielsen

Blankenstein

et al. 2014

Glia

View full text Add to dashboard Cite

Defective clearance of the amyloid-β peptide (Aβ) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aβ clearance and Aβ aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence Aβ clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of Aβ oligomers (Aβoligo ) and Aβ fibrils (Aβfib ), and whether the Aβ aggregation state and/or presence of AAPs affect Aβ uptake in these cells in vitro. Adult human primary microglia and astrocytes, isolated from short delay post-mortem brain tissue, were exposed to either Aβoligo or Aβfib alone or combined with a panel of certain AAPs whereafter Aβ-positive cells were quantified using flow cytometry. Upon exposure to Aβ combined with ApoE, ApoJ, α1-antichymotrypsin (ACT) and a combination of serum amyloid P and complement C1q (SAP-C1q), a clear reduction in astrocytic but not microglial Aβoligo uptake, was observed. In contrast, Aβfib uptake was strongly reduced in the presence of AAPs in microglia, but not in astrocytes. These data provide the first evidence of distinct roles of microglia and astrocytes in Aβ clearance. More importantly we show that Aβ clearance by glial cells is negatively affected by AAPs like ApoE and ApoJ. Thus, targeting the association of Aβ with AAPs, such as ApoE and ApoJ, could serve as a therapeutic strategy to increase Aβ clearance by glial cells.

show abstract

Association of ApoE and LRP mRNA levels with dementia and AD neuropathology

Cited by 34 publications

References 117 publications

Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease

Redefining transcriptional regulation of the APOE gene and its association with Alzheimer’s disease

The cis‐regulatory effect of an Alzheimer's disease‐associated poly‐T locus on expression of TOMM40 and apolipoprotein E genes

Apolipoproteins E and J interfere with amyloid‐beta uptake by primary human astrocytes and microglia in vitro

Contact Info

Product

Resources

About