| The structure of APOE isoforms. APOE is a soluble secreted protein, with N-terminal and C-terminal domains linked by a central hinge region. The N-terminal domain contains the receptor binding domain (indicated in green), and the C-terminal domain contains the lipid binding region (indicated in orange). Each isoform differs from one another at amino acid position 112 and 158. Cysteine at position 158 (C158) in APOE2 is thought to cause deficient receptor binding, while arginine at position 112 (R112) in APOE4 changes the conformation of the entire domain such that R61 is exposed and interacts with C255 in the C-terminal domain (red dotted line). This "domain interaction" is thought to be the biophysical basis for differences in APOE4 function compared to the other isoforms; e.g., preference for VLDL over HDL. In APOE3 and APOE2, which have C112 instead of R112, the R61 is not exposed and there is no such domain interaction.

| The structure of APOE isoforms. APOE is a soluble secreted protein, with N-terminal and C-terminal domains linked by a central hinge region. The N-terminal domain contains the receptor binding domain (indicated in green), and the C-terminal domain contains the lipid binding region (indicated in orange). Each isoform differs from one another at amino acid position 112 and 158. Cysteine at position 158 (C158) in APOE2 is thought to cause deficient receptor binding, while arginine at position 112 (R112) in APOE4 changes the conformation of the entire domain such that R61 is exposed and interacts with C255 in the C-terminal domain (red dotted line). This "domain interaction" is thought to be the biophysical basis for differences in APOE4 function compared to the other isoforms; e.g., preference for VLDL over HDL. In APOE3 and APOE2, which have C112 instead of R112, the R61 is not exposed and there is no such domain interaction.

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APOE4 is the greatest genetic risk factor for late-onset Alzheimer’s disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily...

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... elucidating the role of mouse APOE is informative, it is also critical to understand whether different phenotypes ensue with human APOE variants. Microglia isolated from aged vs. non-aged human postmortem brain for RNA sequencing analysis display an immune-enriched signature that is significantly associated with key traits, including APOE genotype (Olah et al., 2018). Although statistical significance was not reached for APOE4, the neuroprotective APOE2 was associated with a reduction in this aged microglial phenotype ( Olah et al., 2018). ...
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... statistical significance was not reached for APOE4, the neuroprotective APOE2 was associated with a reduction in this aged microglial phenotype ( Olah et al., 2018). In human cellular models, isogenic conversion of human iPSC-derived microglia from APOE3/E3 AD patients to APOE4/E4 is sufficient to transform the microglia transcriptome to a DAM-like phenotype (Lin et al., 2018). Notably, this APOE4 gene expression signature significantly overlapped with the transcriptional profile seen in human brain ( Lin et al., 2018), in support of the notion that APOE4 may impact the DAM phenotype in human AD. ...

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... Interestingly, TREM2 was found to have a vital role in both central and peripheral lipid metabolism. Recent researches have shown that TREM2 can bind to lipid-associated ligands, such as phospholipids [8], high-density lipoproteins, lowdensity lipoproteins (LDL) [22], lipids contained in apoptotic neurons [23], and apolipoprotein E (ApoE), which is an important lipid transporter in the CNS [22,24,25]. These associations indicate a certain relationship between TREM2 and lipids. ...
... All three isoforms can bind to TREM2. APOE ε4 is the largest genetic risk factor for late-onset AD, while APOE ε2 is protective for AD [25,46]. The mouse ApoE protein is most similar to that of human ApoE3, which is the most common form of ApoE protein [48]. ...
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... In addition to its female-specific effects, our genetic analyses demonstrate that sST2/rs1921622 plays disease-causing effects in females with AD, specifically those carrying APOE-ε4, suggesting a potential interaction between IL-33-ST2 signaling and ApoE. In the brain, ApoE is mainly produced by astrocytes, and its expression is upregulated in microglia in AD 53,80 . Single-cell RNA-seq of amyloidosis mouse models revealed that a microglial subpopulation transitions from a homeostatic state to an activated state termed 'disease-associated microglia' or 'activated response microglia' 4,55 , with increased expression of microglial activation genes (including APOE, AXL, TREM2 and CD74) [53][54][55][56] that are crucial regulators of phagocytic processes [81][82][83][84] . ...
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... Understanding the underlying mechanisms of TREM2 and APOE interaction, its impact on synaptic function and cognitive impairment in AD pathogenesis will be important as it will connect two well-validated genetic risk factors [114]. Microglial APOE expression strongly increases during aging and in AD as shown by multiple human and mouse studies [115][116][117]. Currently, data on the effects of APOE on microglial function exist only from mouse studies; human datasets are, as yet, too small to interrogate this question effectively [117]. ...
... Microglial APOE expression strongly increases during aging and in AD as shown by multiple human and mouse studies [115][116][117]. Currently, data on the effects of APOE on microglial function exist only from mouse studies; human datasets are, as yet, too small to interrogate this question effectively [117]. Additional ADspecific risk genes with enriched expression in myeloid cells include the transmembrane receptor CD33, the glycoprotein clusterin and the complement receptor CR1 among others [118,119]. ...
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... Finally, we supplied the 24 common astrocyte affiliated transcripts to produce a STRING interaction network ( Figure 8E). Many of the interacting proteins are widely known to be induced within reactive astrocytes including Gfap (Hol and Pekny, 2015), Apoe (Fernandez et al., 2019), Aqp4 (Ikeshima-Kataoka, 2016), and Clu (Foster et al., 2019). We concluded that astrocyte transcriptional changes to prion infection reflected the overall morphological and oxidative changes that accompany reactive gliosis, and at least partly depend on the different astrocyte populations found in the CA1 and thalamus. ...
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... Compelling evidence suggests that polymorphic variants of APOE gene may correlate with the development of sporadic AD. The presence of the APOE4 allele greatly exacerbates the risk of the disease, while the presence of the APOE2 allele decreases the susceptibility to the disease (Yu et al., 2014;Fernandez et al., 2019). Similarly, current data also indicate various influences of APOE genotypes on αSyn aggregation and APOE4 may exacerbate a series of abnormalities characteristic of PD, such as behavioral disturbances, loss of neural connections and astrogliosis (Zhao et al., 2020). ...
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... All these differences likely play a role in their differential effects on amyloid-beta and tau protein accumulation and clearance as well as the amount of cholesterol efflux at sites, and may also indicate a causal role in myelination ( de Chaves and Narayanaswami, 2008 ;Yanagisawa, 2005 ;Yao and Papadopoulos, 2002 ;Jurevics and Morell, 1995 ;Saher et al., 2011 ). Indeed, APOE is mainly expressed by astrocytes and microglia, two major contributors to myelin synthesis, with studies indicating that APOE 4 alters astrocytes and microglia function ( Fernandez et al., 2019 ;Lanfranco et al., 2021 ). Moreover, it has been shown that APOE protein abundance in human brain follows an isoform-dependent pattern ( 2 > 3 > 4) ( Conejero-Goldberg et al., 2014 ). ...
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Mounting evidence indicates that myelin breakdown may represent an early phenomenon in neurodegeneration, including Alzheimer's disease (AD). Understanding the factors influencing myelin synthesis and breakdown will be essential for the development and evaluation of therapeutic interventions. In this work, we assessed associations between genetic variance in apolipoprotein E (APOE) and cerebral myelin content. Quantitative magnetic resonance imaging (qMRI) was performed on a cohort of 92 cognitively unimpaired adults ranging in age from 24 to 94 years. We measured whole-brain myelin water fraction (MWF), a direct measure of myelin content, as well as longitudinal and transverse relaxation rates (R1 and R2), sensitive measures of myelin content, in carriers of the APOE ε4 or APOE ε2 alleles and individuals with the ε33 genotype. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF or relaxation rates and APOE isoforms, accounting for confounding variables including age, sex, and race, in several cerebral structures. Our results indicate that carriers of APOE ε2 exhibited significantly higher myelin content, that is, higher MWF, R1 or R2 values, in most brain regions investigated as compared to noncarriers, while ε4 carriers exhibited trends toward lower myelin content compared to noncarriers. Finally, all qMRI metrics exhibited quadratic, inverted U-shape, associations with age; attributed to the development of myelination from young to middle age followed by progressive loss of myelin afterwards. Sex and race effects on myelination were, overall, nonsignificant. These findings suggest that individual genetic background may influence cerebral myelin maintenance. Although preliminary, this work lays the foundation for further investigations to clarify the relationship between APOE genotype and myelination, which may suggest potential targets in treatment or prevention of AD.
... However, the association between apoE4 and AD pathogenesis remains ambiguous. Though much of the research has focused on the ability of the apoE4 to increase the aggregation and decrease the clearance of Aβ, a lot of evidences show that apoE4 obviously impacts cholesterol transport and homeostasis in the brain [39,89]. ApoE isoforms exert a central role in controlling the transport of brain lipid, including cholesterol, and maintaining cholesterol homeostasis in the brain [89]. ...
... ApoE isoforms exert a central role in controlling the transport of brain lipid, including cholesterol, and maintaining cholesterol homeostasis in the brain [89]. Moreover, the accelerated degradation of apoE4 by astrocytes and neurons, resulting in decreased apoE4 levels in the brain [39,89,147]. In apoE4 mice, with the reduced secretion of apoE4 by astrocytes, Astrocytes secreted 34% less cholesterol than those from wild-type mice, the amounts of total cholesterol were significantly decreased compared with the wild-type littermates [48,158]. ...
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Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.
... There are two main sources of production of ApoE. In the periphery, the majority of circulating ApoE is synthesized by the liver [99], while in the central nervous system (CNS), it is mainly produced by glial cells [100]. Peripheral ApoE plays a critical role in lipid metabolism by transporting lipoproteins into the lymph system and blood and maintaining the cellular uptake of lipoproteins via its primary receptor LDLR (lowdensity lipoprotein receptor) [101,102]. ...
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... In humans, the brain is the most cholesterol rich organ and synthesizes its own cholesterol. In the brain, APOE protein is mainly produced by astrocytes and is abundantly expressed in neurons and microglia under stress or injury conditions ( Fernandez et al., 2019 ). ...
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Apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. This study sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n=411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (P=0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (P=0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline.
... The shift in microglia activation to a reactive or DAM/MGnD state has been shown to be apoE dependent [28,29,[68][69][70]. Furthermore, astrocytic apoE lipoprotein particles can influence microglial activation [71,72], and our results support the hypothesis that astrocytic apoE may be involved in signaling pathways between astrocytes and microglia that regulate the apoE-dependent DAM activation state of microglia. The transition to the DAM activation state has been shown to be TREM2-APOE dependent [28] and apoE is a ligand for TREM2 [73][74][75]. ...
... The impact of apoE on microgliosis at sites of Aβ plaque deposition can lead to changes in damage to surrounding cells, including the formation of dystrophic neurites (neuritic dystrophy) [72]. Neuritic dystrophy has been shown to be increased around fibrillar plaques with a more dispersed morphology than around dense core plaques with a compact morphology [24,66,[77][78][79]. ...
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Background: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods: We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results: Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion: This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.