Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma

Baker-Nigh, Alaina; Mawuenyega, Kwasi G.; Bollinger, James G.; Ovod, Vitaliy; Kasten, Tom; Franklin, Erin; Liao, Fan; Jiang, Hong; Holtzman, David M.; Cairns, Nigel J.; Morris, John C.; Bateman, Randall J.

doi:10.1074/jbc.m116.721779

Cited by 44 publications

(54 citation statements)

References 62 publications

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“…Additionally, we failed to detect any changes in the degree of astrogliosis or microgliosis immediately surrounding the plaques between APP/PS1/ EKI Cre mice and their Cre −/− littermates (data not shown). Altogether, our data suggest CNS-and peripherally-derived apoE exist in distinct pools that are independent from one another, as has been suggested in human studies [92]. However, we cannot rule out other hypotheses that would otherwise explain the lack of any appreciable effect on Aβ in APP/PS1/EKI Cre mice, such as an unknown adaptive response that masked the contribution of hepatic apoE to brain Aβ pathology.…”

Section: Discussionsupporting

confidence: 56%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

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Section: Discussionsupporting

confidence: 56%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

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“…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

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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.

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“…The mass spectrometry approaches tend to show similar general trends, but with smaller effect sizes. That is, APOE genotype-dependent differences in APOE protein levels appear less pronounced in mass spectrometry studies compared to ELISA-based methods, supporting concerns about isoform-specific binding preference in ELISA (Baker-Nigh et al, 2016;Rasmussen et al, 2015). Given the limited sample sizes, differing strategies in lipoprotein extraction, and varying analytical standards of these mass spectrometry studies, future large-scale studies are needed to determine the optimal measurement technique.…”

Section: Quality?mentioning

confidence: 98%

“…Most approaches make use of ELISA-based strategies for APOE detection, but these are hobbled by intrinsic assay variability, bias from antibody isoform-specific binding preference, and a lack of isoform specificity (Baker-Nigh et al, 2016;Martínez-Morillo et al, 2014a). In response to these concerns, a few studies have used mass spectrometry approaches to decrease measurement bias (Baker-Nigh et al, 2016;Martínez-Morillo et al, 2014a, 2014b. The mass spectrometry approaches tend to show similar general trends, but with smaller effect sizes.…”

Section: Quality?mentioning

confidence: 99%

“…Some have shown a similar APOE2 > APOE3 > APOE4 effect on CSF APOE levels (Cruchaga et al, 2012;Toledo et al, 2014), but others have not (Bekris et al, 2008;Talwar et al, 2016). CSF APOE measurements also appear to vary with age, sex, and with the amount of beta-amyloid in the CSF (Baker-Nigh et al, 2016;Bekris et al, 2008;Cruchaga et al, 2012;Darreh-Shori et al, 2011;Toledo et al, 2014). A step closer to the pathological substrate, findings on brain APOE levels have also been marked by heterogeneity.…”

Section: Quality?mentioning

confidence: 99%

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A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Belloy

Napolioni

Greicius

2019

Neuron

349

316

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Alzheimer's disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi ''monogenic'' role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD. (A) The three main APOE isoforms APOE2, APOE3, and APOE4, respectively, encoded by the Apolipoprotein E2, E3, and E4 alleles, are the result of non-synonymous polymorphisms that cause amino acid changes at position 112 and 158 of the APOE protein (Rall et al., 1982; Weisgraber et al., 1981). APOE3 is the most common variant in the general population. The APOE4 variant is a major genetic risk factor for AD, while APOE2 is protective (Farrer et al., 1997). (B) Structural models of lipid-free APOE are shown for each major isoform, based on X-ray crystallography, structure prediction, and circular dichroism spectroscopy (Zhong and Weisgraber, 2009). The N-terminal domain contains APOE's low-density lipoprotein receptor (LDLR) region at amino acid residues 134-150, while the C-terminal holds the lipid-binding region at residues 244-272. Amino acid substitutions in APOE4 promote a salt bridge between Arg61 and Glu255, which, compared to the APOE2 and APOE3 variants, drives increased domain interaction between the N-and C-terminal domains. In (A), APOE allele frequencies are obtained, with permission, from American

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Human Central Nervous System (CNS) ApoE Isoforms Are Increased by Age, Differentially Altered by Amyloidosis, and Relative Amounts Reversed in the CNS Compared with Plasma

Abstract: "Human central nervous system (CNS) ApoE isoforms are increased by age, differentially altered by amyloidosis, and relative amounts reversed in the CNS compared with plasma."

Cited by 44 publications

References 62 publications

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

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

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

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