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Mol. Cells 2019; 42(11): 739-746
Published online November 12, 2019
https://doi.org/10.14348/molcells.2019.0200
© The Korean Society for Molecular and Cellular Biology
ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer’s Disease
Correspondence to : jsseo@dgist.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Abstract
Significant knowledge about the pathophysiology of Alzheimer’s disease (AD) has been gained in the last century; however, the understanding of its causes of onset remains limited. Late-onset AD is observed in about 95% of patients, and
Keywords Aβ, Alzheimer’s disease, ApoE4, apolipoprotein, cholesterol
INTRODUCTION
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is one of the most common forms of irreversible dementia. Patients with AD suffer from cognitive impairment including language problems, mood changes, as well as memory loss. AD brains display amyloid-beta (Aβ) plaques, tau tangles, synaptic degradation, and neuronal loss. Among these neurobiological changes, Aβ plaque is considered to be one of the major hallmarks of AD because of its early appearance during the progression of the disease. Therefore, a major focus of ongoing research has been identifying the mechanisms of Aβ plaque formation and aggregation to target Aβ metabolism (O’Brien and Wong, 2011; Selkoe and Hardy, 2016). Although many studies and clinical trials for candidate drugs are currently underway, it is not yet clear how AD progresses, and no effective treatment for the disease exists. Currently-available drugs such as cholinesterase inhibitors only delay the onset of symptoms.
While early-onset AD pathology has been shown to be associated with genetic mutations in coding regions for proteins involved in Aβ metabolism (e.g., amyloid precursor protein;
ApoE is an apolipoprotein that plays a major role in cholesterol transport. In the brain, ApoE was previously believed to be mainly produced by astrocytes (Zhang et al., 2014; 2016). However, recent transcriptome analysis from human brain samples and hiPSC-derived brain cell types showed considerable expression of ApoE transcripts in microglia as well, and its expression is upregulated even in neurons in AD brains (Keren-Shaul et al., 2017; Lin et al., 2018; Mathys et al., 2019; Xu et al., 2006). There are three isoforms of ApoE; ApoE2, ApoE3, and ApoE4; only one or two amino acid variations differentiate these isoforms. ApoE3, the most common isoform present in about 78% of the population, has cysteine and arginine residues Cys112 and Arg158, whereas ApoE2 contains cysteine residues Cys112 and Cys158, and ApoE4 carries two arginine residues, Arg112 and Arg158. Although the difference is very subtle, it results in drastically differential effects on the risk for AD development. The allele frequency of ApoE2 is about 8%, and it is known to be neuroprotective. However, ApoE4 is one of the strongest risk factors for AD with a prevalence of about 14% (Liu et al., 2013; Strittmatter et al., 1993). Since its strong association with AD was first reported about twenty-five years ago (Corder et al., 1993; Strittmatter et al., 1993), many studies have been dedicated to determining how only one amino acid alteration in ApoE4 compared to ApoE3 could drastically increase the risk of AD (Liu et al., 2013).
In terms of the role of ApoE protein on Aβ metabolism, contradictory data have been reported in different studies. Some studies have reported a decrease in Aβ plaque in familial AD (fAD) mouse models with ApoE deficiency, while others showed that ApoE is required for Aβ reduction, including astrocyte-mediated Aβ clearance, and deletion of ApoE accelerated the accumulation of fibrillar amyloid in the brains of fAD mice (Bales et al., 1997; Holtzman et al., 1999; 2000; Kim et al., 2011; Koistinaho et al., 2004; Tai et al., 2011; Ulrich et al., 2018). Regarding the role of ApoE isoforms in AD pathogenesis, most studies agree that ApoE4 induces the highest Aβ accumulation and gliosis compared with other isoforms (Lin et al., 2018; Liu et al., 2013; 2017). Hyperphosphorylation of tau and related pathology (tauopathy), another hallmark of AD, has also been observed to be accelerated in the presence of the ApoE4 isoform (Shi et al., 2017). However, the mechanisms of ApoE4-induced AD pathogenesis still remain unclear.
Recent evidence has emerged showing abnormal cholesterol metabolism by ApoE4 could mediate AD-associated pathology. Here, we review recent research, providing some insights on how ApoE4-mediated cholesterol dysregulation could affect functions of different brain cell types in the context of AD.
NEURONS
Neurons are the most vulnerable to the toxicity of Aβ accumulation, and they are also the major cell type responsible for generating Aβ in the brain (Sinha and Lieberburg, 1999; Zhang et al., 2016). Various pathological features are induced by Aβ accumulation in neurons, such as synaptic degradation, altered synaptic and neuronal circuit activity, and cell death, which have been extensively reviewed elsewhere (Canter et al., 2016; De Strooper and Karran, 2016; Palop and Mucke, 2010; Selkoe and Hardy, 2016). In this review, we focus on how ApoE4-induced cholesterol metabolic abnormalities could affect Aβ generation and alter the synaptic function in neurons.
Neuronal lipid rafts provide the platform for APP to encounter its cleaving enzymes, resulting in Aβ generation. Cholesterol is one of the major components of lipid rafts, and its dysregulation affects Aβ production in neurons (Fassbender et al., 2001; Simons et al., 1998). Tethering of cholesterol to methyl-β-cyclodextrin (MβCD) enables its delivery to the plasma membrane, and neurons treated with MβCD-cholesterol complex show increased lipid raft formation and generation of Aβ (Cossec et al., 2010; Marquer et al., 2014). However, it remains unknown whether cholesterol-dependent facilitation of Aβ cleavage is through the regulation of β-secretase activity or/and increased formation of APP/β-secretase clusters (Kalvodova et al., 2005; Marquer et al., 2011). Some genetic variants associated with the LOAD are found on or near genes related to cholesterol transport such as
In the brain, cholesterol is mainly transmitted from astrocytes to neurons via lipoprotein particles, of which ApoE is one of the major components (Liu et al., 2013; Vance, 2012). ApoE, mainly produced by astrocytes, forms the lipoprotein complex with cholesterol and is secreted through the function of ABCAs. Among isoforms, ApoE4 displays lower transport affinity and binding capacity for lipids (Hatters et al., 2006; Vance, 2012), which could reduce cholesterol transport from astrocytes to neurons. As a result, the formation of neuronal lipid rafts and Aβ production might be affected by ApoE4 in the brain. Two recent studies with astrocytes generated from hiPSCs addressed this point, and both showed higher accumulation of cholesterol in ApoE4-expressing astrocytes than in isogenic ApoE3 astrocytes (Lin et al., 2018; TCW et al., 2019). However, regarding the secretion of cholesterol from these ApoE4 astrocytes, Lin et al. (2018) showed increased extracellular cholesterol levels by directly measuring secreted cholesterol in cultured media, while TCW et al. (2019) speculated that ApoE4 astrocytes might secrete less cholesterol due to a reduction of ApoE and Abca1, which mediate the efflux of cholesterol. Further studies are required to directly examine cholesterol transport to neurons from astrocytes with different ApoE isoforms.
Although cholesterol synthesis in neurons is lower than in astrocytes, particularly in adults (Nieweg et al., 2009; Pfrieger and Ungerer, 2011), ApoE isoform-dependent changes in cholesterol metabolism in neurons could also be driven in a cell-autonomous manner. For example, impaired efflux of cholesterol in ApoE4 neurons could contribute to its intracellular accumulation, leading to AD-related pathology, as observed in mice with cholesterol 24-hydroxylase-dependent cholesterol efflux suppressed in hippocampal neurons (Djelti et al., 2015). It is also important to investigate whether ApoE4 neurons have altered the expression and/or function of ApoE receptors such as those belonging to the low-density lipoprotein receptor family that can directly affect the uptake of extracellular cholesterol as well as Aβ clearance (Holtzman et al., 2012).
Cholesterol plays critical roles in synaptic function. It helps maintain adequate curvature of membrane to facilitate soluble NSF attachment protein receptor (SNARE)-mediated membrane fusion. Depleting cholesterol significantly reduces synaptic transmission, which can be reversed by reloading cholesterol (Linetti et al., 2010; Tong et al., 2009). Lack of cholesterol in neurons leads to impaired synaptic plasticity, evidenced by changes in paired-pulse facilitation and long-term potentiation (Koudinov and Koudinova, 2002). Hippocampal synapses in mice with decreased astrocytic cholesterol secretion also showed fewer synaptic vesicles, more immature synapses, and reduced expression of presynaptic synaptosomal nerve-associated protein 25 (SNAP-25) required for the exocytic release of neurotransmitters (van Deijk et al., 2017).
The role of ApoE isoforms on the formation of neuronal synapses and their function is not yet clear (Kim et al., 2014). A recent study with ApoE2, ApoE3 and ApoE4 knock-in (KI) mice in which the murine
ASTROCYTES
Lipoprotein-bound cholesterol from circulating plasma is prevented from entering the brain due to the presence of the blood-brain barrier (BBB), and astrocytes, which account for up to 40% of all brain cells in humans, are mainly responsible for producing cholesterol in the brain (Nieweg et al., 2009; Zhang et al., 2016). Cholesterol synthesis in astrocytes is tightly regulated by an internal feedback loop; if the intracellular level of cholesterol is low, cholesterol synthesis is induced by increasing proteolytic processes of sterol regulatory element-binding proteins (SREBPs) and reducing levels of proteins that mediate cholesterol efflux (Benarroch, 2008). When the intracellular cholesterol level is high, liver X receptor/retinoid X receptor (LXR/RXR)-mediated transcription for cholesterol transport proteins is increased, and efflux of lipoprotein complex is facilitated (Fig. 1). Cholesterol accumulation in ApoE4 astrocytes may not be due, solely, to impaired efflux resulting from reduced ApoE levels. Transcriptome analysis in hiPSC-derived astrocytes suggests the expression of genes involved in lipid metabolism is dysregulated in ApoE4 astrocytes, with an increase in the expression levels of cholesterol biosynthesis-related genes. Lysosomal cholesterol degradation processes also seem to be impaired in these cells (Lin et al., 2018; TCW et al., 2019). Further study is required to precisely elucidate the mechanisms underlying ApoE4-induced cholesterol accumulation in astrocytes, and how it can be targeted to resolve the abnormality.
Because cholesterol is a multifunctional metabolite, abnormal cholesterol metabolism by ApoE4 would lead not only altered cholesterol transport to other cell types but also functional deficits in astrocytes as observed in neurons (Fukui et al., 2015; Martín-Segura et al., 2019) and microglia (Churchward and Todd, 2014; Račková, 2013). However, there have not been many studies investigating the effects of intracellular cholesterol on cellular functions or formation of organelles in astrocytes. Therefore, investigating whether/how ApoE4 induces cholesterol-related cellular alterations in astrocytes are a priority. Cholesterol levels in astrocytes and glucose metabolism are closely linked (Ferris et al., 2017), A recent study showed ApoE isoform-dependent changes of brain glucose metabolism in mice (Wu et al., 2018), and it suggests that cholesterol abnormalities caused by ApoE4 could alter glucose metabolism (Fig. 1). Since astrocytes provide not only structural but metabolic supports for neurons, further investigations of astrocyte-specific changes in glucose metabolism in humanized ApoE KI mouse models or single-cell type culture systems with different ApoE isoforms, and its association with cholesterol dysregulation are needed.
MICROGLIA
The role of microglia in AD has been extensively investigated; nonetheless, their precise contribution to the development of AD pathology remains unclear. A recent development in single-cell transcriptome analysis technology revealed the spectrum of microglia phenotypes during AD pathogenesis and the species difference in transcriptomic information of disease-associated microglia between mice and humans (Keren-Shaul et al., 2017; Mathys et al., 2017; 2019). Although this topic is of great interest, it is beyond the scope of this review. Nevertheless, it is important to note that in both mouse and human cells, ApoE, along with triggering receptor expressed on myeloid cells 2 (TREM2), is shown to be upregulated and mediates microglial phenotypic changes and recruitment to amyloid plaques during the progression of AD (Cheng-Hathaway et al., 2018; Keren-Shaul et al., 2017; Parhizkar et al., 2019; Ulrich et al., 2018). Transition of microglia from resting (homeostatic) to reactive (disease-associated) phenotypes is generally mediated by transcriptional regulation (Deczkowska et al., 2018; Holtman et al., 2017; Krasemann et al., 2017). Although ApoE isoform-dependent transcriptional regulation was recently suggested by multiple studies (Huang et al., 2017; Lin et al., 2018; TCW et al., 2019), its precise mechanism is unclear.
Because excessive inflammatory response is associated with AD, the relationship between the level of cholesterol and immune responses in microglia, the brain resident macrophages, is of great interest. Interaction of cholesterol and inflammatory response in macrophages was suggested (Ricote et al., 2004). In microglia, however, regulation of inflammatory responses by peroxisome proliferator-activated receptor γ (PPARγ), LXR/RXR-mediated cholesterol synthesis, and phagocytic activity by PPARγ and LXR/RXR were reported in separate studies (Bernardo and Minghetti, 2006; Courtney and Landreth, 2016; Saijo et al., 2013; Savage et al., 2015). Direct interaction between cholesterol and inflammatory responses in this cell type has not been assessed.
The effect of microglial cholesterol on AD pathogenesis has been previously investigated using primary cultured cells. In primary microglia, accumulation of intracellular cholesterol induced by either MβCD-mediated loading or Niemann–Pick disease, type C1 (NPC1) inhibition (thus blocking cholesterol export from the lysosome) also increases intracellular Aβ. Furthermore, a negative correlation between cholesterol accumulation-induced intracellular Aβ and ApoE levels in these cells was observed. These data suggest that ApoE contributes to intracellular Aβ clearance through the regulation of cholesterol levels in microglia (Lee et al., 2012).
Recently developed protocols to generate microglia-like cells from hiPSC have enabled researchers to investigate functions and underlying mechanisms of ApoE4 variants in human microglia (Abud et al., 2017; Muffat et al., 2016; Pandya et al., 2017). Microglia-like cells from hiPSC carrying the
OLIGODENDROCYTES
Oligodendrocytes have a unique structure called myelin that ensheathes axons, facilitating conduction of action potentials and protecting neurons from other possible extracellular insults (Domingues et al., 2016). Lipids are the major components of myelin membranes, consisting of at least 70% of their dry weight, whereas membranes in other cell types are generally composed of about 30% lipids and 70% proteins (Chrast et al., 2011; Ingólfsson et al., 2017). This suggests that altered lipid composition by abnormal metabolic processes would affect not only intracellular compartments generally seen in other cell types but also the formation and function of myelin, which is critical for neuronal function.
Among lipid metabolites in myelin membranes, cholesterol has been shown to have a significant role in myelin formation. Inhibition of cholesterol-synthesizing ability in oligodendrocytes by deleting squalene synthases leads to a significant reduction of myelination in oligodendrocytes, inducing behavioral abnormalities such as ataxia and tremors in mice (Saher et al., 2005). Increased levels of gene expression associated with cholesterol biosynthesis were also observed in oligodendrocyte lineage cells during the remyelination phase following axonal damage (Voskuhl et al., 2019). These data demonstrate the major contribution of oligodendrocyte-derived cholesterol for myelination in the brain. A recent study also reported the role of astrocytic cholesterol in the formation of myelin following axonal injury (Camargo et al., 2017). In this study, cell type-specific deletion of SREBP cleavage-activating protein (SCAP), which mediates cholesterol synthesis, either in oligodendrocytes or astrocytes, showed only partial impairment of myelination in mice. When SCAP is ablated in both cell types, however, mice showed an almost complete absence of myelination in the brain. These results suggest that altered levels of extracellular and intracellular cholesterol for oligodendrocytes could regulate myelination in the brain.
As a major cholesterol transporter, it would not be surprising that ApoE is involved in myelination processes. Indeed, a recent study showed that ApoE is required for cholesterol clearance in demyelinating lesions to prevent lysosomal accumulation of myelin debris (Cantuti-Castelvetri et al., 2018). Studies have found an association between amyloid pathology with myelin alteration in AD animal models and preclinical studies, including a reduction of myelination associated with brain atrophy (Dean et al., 2017; Wu et al., 2017). Further work is needed to determine the differential role of ApoE isoforms in oligodendrocytes and whether and how ApoE4-associated cholesterol dysregulation in these cells drive AD-associated pathology.
CONCLUSION
Investigating pathological features of whole AD brain samples would be of interest. However, it is also necessary to tease out cell type-specific alterations and their contributions to AD pathogenesis. Recent investigations of cell type-specific functions of ApoE4 from various brain cell types isolated from ApoE KI mice or derived from hiPSC showed impaired cholesterol metabolism by ApoE4, specifically in glial cells that were not evident from previous studies that relied on bulk brain samples composed of mixed cell populations (Lin et al., 2018; Nuriel et al., 2017; TCW et al., 2019). As we reviewed, cholesterol metabolism is closely linked to various functions in different types of cells in the brain, and its dysregulation can lead to AD-associated pathological phenotypes in each cell type, including Aβ upregulation in neurons, abnormal glucose metabolism in astrocytes, inflammatory responses in microglia, and myelination defects in oligodendrocytes (Fig. 2).
In addition to these cell types, the BBB, which is composed of various cell types, including pericytes and endothelial cells, was also shown to be influenced by ApoE4. Multiple studies suggest that ApoE4 leads to BBB leakage through the degeneration of pericytes and the disruption of the integrity of tight junctions (Casey et al., 2015; Nishitsuji et al., 2011), which leads to the accumulation of serum proteins in the brain (Bell et al., 2012). This can result in further elevation of brain cholesterol. It is also possible that increased cholesterol in the brain or plasma by ApoE4 affects BBB integrity and may lead to leakage (Jiang et al., 2012; Kalayci et al., 2009). While there is a close coupling between neurovascular dysfunction and AD, the cell types mentioned above are understudied in the context of AD. Exploring detailed mechanisms in BBB pathogenesis in ApoE4 brain may provide insights into a new therapeutic avenue.
While we largely discuss ApoE4 as an AD risk factor in terms of cholesterol metabolism in the brain, it is also important to mention that in several studies it has been suggested that plasma cholesterol level and AD risk/pathology are linked (Pappolla et al., 2003; Wingo et al., 2019). Epidemiological studies show an increased concentration of plasma cholesterol in AD patients (Wood et al., 2014), and diet-induced hypercholesterolemia in AD mouse models leads to increased Aβ and impaired memory (Park et al., 2013). Unlike physiological conditions in which the translocation of peripheral cholesterol to the brain is limited, it is facilitated when leakage of the BBB occurs under pathological conditions. Although more studies are necessary to identify plasma cholesterol as a causative factor, it is important to understand the dynamic relationship between brain cholesterol and plasma cholesterol in terms of AD pathogenesis.
Further studies are also required to determine whether other AD genetic risk factors associated with cholesterol homeostasis, including Clustrin (apolipoprotein J) and
ACKNOWLEDGMENTS
This work was supported by DGIST MIREBraiN program and the National Research Foundation of Korea (NRF) grants (2018M3C7A1056275). We thank Joonho Cho for careful reading of the manuscript and helpful comments.
FIGURES
Fig. 1. Intracellular cholesterol level is tightly regulated and maintained in astrocytes, major producers of cholesterol in the brain. When cholesterol level is low, SREBP-mediated cholesterol synthesis is triggered. If the level of cholesterol is increased, SREBP is suppressed and LXR/RXR-induced transcription for cholesterol transport proteins such as ApoE and Abca1 is facilitated. Cholesterol is also synthesized from glucose-derived Acetyl CoA, and the level of cholesterol can affect glucose metabolism.
Fig. 2. Cholesterol dysregulation by ApoE4 could lead to cell type-specific functional abnormalities in the brain such as Aβ upregulation and impaired synaptic function in neurons, reduced synapse prunning activity in astrocytes, impaired remyelination in oligodendrocytes, and Aβ accumulation and inflammatory response in microglia.
REFERENCES
- Abud, E.M., Ramirez, R.N., Martinez, E.S., Healy, L.M., Nguyen, C.H.H., Newman, S.A., Yeromin, A.V., Scarfone, V.M., Marsh, S.E., and Fimbres, C. (2017). iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 94, 278-293.e9.
- Baik, S.H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.I., and Mook-Jung, I. (2019). A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 30, 493-507.e6.
- Bales, K.R., Verina, T., Dodel, R.C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E.M., Little, S.P., and Cummins, D.J. (1997). Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 17, 263-264.
- Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M., Betsholtz, C., Armulik, A., and Sallstrom, J. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 485, 512-516.
- Benarroch, E.E. (2008). Brain cholesterol metabolism and neurologic disease. Neurology. 71, 1368-1373.
- Bernardo, A. and Minghetti, L. (2006). PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des. 12, 93-109.
- Camargo, N., Goudriaan, A., van Deijk, A.L.F., Otte, W.M., Brouwers, J.F., Lodder, H., Gutmann, D.H., Nave, K.A., Dijkhuizen, R.M., and Mansvelder, H.D. (2017). Oligodendroglial myelination requires astrocyte-derived lipids. PLoS Biol. 15, e1002605.
- Canter, R.G., Penney, J., and Tsai, L.H. (2016). The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature. 539, 187-196.
- Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.T., Su, M., Sen, P., Ruhwedel, T., Mitkovski, M., Trendelenburg, G., and Lütjohann, D. (2018). Defective cholesterol clearance limits remyelination in the aged central nervous system. Science. 359, 684-688.
- Casey, C.S., Atagi, Y., Yamazaki, Y., Shinohara, M., Tachibana, M., Fu, Y., Bu, G., and Kanekiyo, T. (2015). Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA protein-mediated pathway. J Biol Chem. 290, 14208-14217.
- Cheng-Hathaway, P.J., Reed-Geaghan, E.G., Jay, T.R., Casali, B.T., Bemiller, S.M., Puntambekar, S.S., von Saucken, V.E., Williams, R.Y., Karlo, J.C., and Moutinho, M. (2018). The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer’s disease. Mol Neurodegener. 13, 29.
- Chrast, R., Saher, G., Nave, K.A., and Verheijen, M.H.G. (2011). Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res. 52, 419-434.
- Chu, C.S., Tseng, P.T., Stubbs, B., Chen, T.Y., Tang, C.H., Li, D.J., Yang, W.C., Chen, Y.W., Wu, C.K., and Veronese, N. (2018). Use of statins and the risk of dementia and mild cognitive impairment: a systematic review and meta-analysis. Sci Rep. 8, 5804.
- Chung, W.S., Verghese, P.B., Chakraborty, C., Joung, J., Hyman, B.T., Ulrich, J.D., Holtzman, D.M., and Barres, B.A. (2016). Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 113, 10186-10191.
- Churchward, M.A. and Todd, K.G. (2014). Statin treatment affects cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms. Mol Brain. 7, 85.
- Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., and Pericak-Vance, M.A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 261, 921-923.
- Cossec, J.C., Simon, A., Marquer, C., Moldrich, R.X., Leterrier, C., Rossier, J., Duyckaerts, C., Lenkei, Z., and Potier, M.C. (2010). Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta. 1801, 846-852.
- Courtney, R. and Landreth, G.E. (2016). LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol Metab. 27, 404-414.
- De Strooper, B. and Karran, E. (2016). The cellular phase of Alzheimer’s disease. Cell. 164, 603-615.
- Dean, D.C., Hurley, S.A., Kecskemeti, S.R., O’Grady, J.P., Canda, C., Davenport-Sis, N.J., Carlsson, C.M., Zetterberg, H., Blennow, K., and Asthana, S. (2017). Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 74, 41-49.
- Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., and Amit, I. (2018). Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 173, 1073-1081.
- Di Paolo, G. and Kim, T.W. (2011). Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci. 12, 284-296.
- Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bièche, I., Marquer, C., Chali, F., Ayciriex, S., and Auzeil, N. (2015). CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease. Brain. 138, 2383-2398.
- Domingues, H.S., Portugal, C.C., Socodato, R., and Relvas, J.B. (2016). Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol. 4, 71.
- Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., and von Bergmann, K. (2001). Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 98, 5856-5861.
- Ferris, H.A., Perry, R.J., Moreira, G.V., Shulman, G.I., Horton, J.D., and Kahn, C.R. (2017). Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A. 114, 1189-1194.
- Fukui, K., Ferris, H.A., and Kahn, C.R. (2015). Effect of cholesterol reduction on receptor signaling in neurons. J Biol Chem. 290, 26383-26392.
- Hatters, D.M., Peters-Libeu, C.A., and Weisgraber, K.H. (2006). Apolipoprotein E structure: insights into function. Trends Biochem Sci. 31, 445-454.
- Holtman, I.R., Skola, D., and Glass, C.K. (2017). Transcriptional control of microglia phenotypes in health and disease. J Clin Invest. 127, 3220-3229.
- Holtzman, D.M., Bales, K.R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A.M., Chang, L.K., Sun, Y., and Paul, S.M. (1999). Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest. 103, R15-R21.
- Holtzman, D.M., Fagan, A.M., Mackey, B., Tenkova, T., Sartorius, L., Paul, S.M., Bales, K., Ashe, K.H., Irizarry, M.C., and Hyman, B.T. (2000). Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol. 47, 739-747.
- Holtzman, D.M., Herz, J., and Bu, G. (2012). Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2, a006312.
- Huang, Y.W.A., Zhou, B., Wernig, M., and Südhof, T.C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. 168, 427-441.e21.
- Ingólfsson, H.I., Carpenter, T.S., Bhatia, H., Bremer, P.T., Marrink, S.J., and Lightstone, F.C. (2017). Computational lipidomics of the neuronal plasma membrane. Biophys J. 113, 2271-2280.
- Jiang, X., Guo, M., Su, J., Lu, B., Ma, D., Zhang, R., Yang, L., Wang, Q., Ma, Y., and Fan, Y. (2012). Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. Int J Alzheimers Dis. 2012, 109324-109327.
- Kalayci, R., Kaya, M., Uzun, H., Bilgic, B., Ahishali, B., Arican, N., Elmas, I., and Küçük, M. (2009). Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats. Int J Neurosci. 119, 1881-1904.
- Kalvodova, L., Kahya, N., Schwille, P., Ehehalt, R., Verkade, P., Drechsel, D., and Simons, K. (2005). Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem. 280, 36815-36823.
- Karch, C.M. and Goate, A.M. (2015). Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 77, 43-51.
- Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D., and Toth, B. (2017). A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 169, 1276-1290.e17.
- Kim, J., Jiang, H., Park, S., Eltorai, A.E.M., Stewart, F.R., Yoon, H., Basak, J.M., Finn, M.B., and Holtzman, D.M. (2011). Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci. 31, 18007-18012.
- Kim, J., Yoon, H., Basak, J., and Kim, J. (2014). Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cells. 37, 767-776.
- Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., and Bales, K.R. (2004). Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 10, 719-726.
- Koudinov, A.R. and Koudinova, N.V. (2002). Cholesterol’s role in synapse formation. Science. 295, 2213.
- Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., and Fanek, Z. (2017). The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 47, 566-581.e9.
- Kunkle, B.W., Grenier-Boley, B., Sims, R., Bis, J.C., Damotte, V., Naj, A.C., Boland, A., Vronskaya, M., van der Lee, S.J., and Amlie-Wolf, A. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 51, 414-430.
- Lambert, J.C., Ibrahim-Verbaas, C.A., Harold, D., Naj, A.C., Sims, R., Bellenguez, C., DeStafano, A.L., Bis, J.C., Beecham, G.W., and Grenier-Boley, B. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 45, 1452-1458.
- Lee, C.Y.D., Tse, W., Smith, J.D., and Landreth, G.E. (2012). Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem. 287, 2032-2044.
- Li, Y., Liu, Q., Sun, J., Wang, J., Liu, X., and Gao, J. (2018). Mitochondrial protective mechanism of simvastatin protects against amyloid β peptide-induced injury in SH-SY5Y cells. Int J Mol Med. 41, 2997-3005.
- Lin, Y.T., Seo, J., Gao, F., Feldman, H.M., Wen, H.L., Penney, J., Cam, H.P., Gjoneska, E., Raja, W.K., and Cheng, J. (2018). APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 98, 1141-1154.e7.
- Linetti, A., Fratangeli, A., Taverna, E., Valnegri, P., Francolini, M., Cappello, V., Matteoli, M., Passafaro, M., and Rosa, P. (2010). Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci. 123, 595-605.
- Liu, C.C., Liu, C.C., Kanekiyo, T., Xu, H., and Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 9, 106-118.
- Liu, C.C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.W., and Bu, G. (2017). ApoE4 accelerates early seeding of amyloid pathology. Neuron. 96, 1024-1032.e3.
- Marquer, C., Devauges, V., Cossec, J.C., Liot, G., Lécart, S., Saudou, F., Duyckaerts, C., Lévêque-Fort, S., and Potier, M.C. (2011). Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J. 25, 1295-1305.
- Marquer, C., Laine, J., Dauphinot, L., Hanbouch, L., Lemercier-Neuillet, C., Pierrot, N., Bossers, K., Le, M., Corlier, F., and Benstaali, C. (2014). Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Mol Neurodegener. 9, 60.
- Martín-Segura, A., Ahmed, T., Casadomé-Perales, Á, Palomares-Perez, I., Palomer, E., Kerstens, A., Munck, S., Balschun, D., and Dotti, C.G. (2019). Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization. Aging Cell. 18, e12932.
- Mathys, H., Adaikkan, C., Gao, F., Young, J.Z., Manet, E., Hemberg, M., De Jager, P.L., Ransohoff, R.M., Regev, A., and Tsai, L.H. (2017). Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366-380.
- Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J.Z., Menon, M., He, L., Abdurrob, F., and Jiang, X. (2019). Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 570, 332-337.
- Muffat, J., Li, Y., Yuan, B., Mitalipova, M., Omer, A., Corcoran, S., Bakiasi, G., Tsai, L.H., Aubourg, P., and Ransohoff, R.M. (2016). Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 22, 1358-1367.
- Nieweg, K., Schaller, H., and Pfrieger, F.W. (2009). Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem. 109, 125-134.
- Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., and Michikawa, M. (2011). Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem. 286, 17536-17542.
- Nuriel, T., Angulo, S.L., Khan, U., Ashok, A., Chen, Q., Figueroa, H.Y., Emrani, S., Liu, L., Herman, M., and Barrett, G. (2017). Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nat Commun. 8, 1464.
- O’Brien, R.J. and Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 34, 185-204.
- Palop, J.J. and Mucke, L. (2010). Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 13, 812-818.
- Pandya, H., Shen, M.J., Ichikawa, D.M., Sedlock, A.B., Choi, Y., Johnson, K.R., Kim, G., Brown, M.A., Elkahloun, A.G., and Maric, D. (2017). Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 20, 753-759.
- Pappolla, M.A., Bryant-Thomas, T.K., Herbert, D., Pacheco, J., Fabra Garcia, M., Manjon, M., Girones, X., Henry, T.L., Matsubara, E., and Zambon, D. (2003). Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 61, 199-205.
- Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., and Katzmarski, N. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 22, 191-204.
- Park, S.H., Kim, J.H., Choi, K.H., Jang, Y.J., Bae, S.S., Choi, B.T., and Shin, H.K. (2013). Hypercholesterolemia accelerates amyloid β-induced cognitive deficits. Int J Mol Med. 31, 577-582.
- Pfrieger, F.W. and Ungerer, N. (2011). Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res. 50, 357-371.
- Račková, L. (2013). Cholesterol load of microglia: contribution of membrane architecture changes to neurotoxic power?. Arch Biochem Biophys. 537, 91-103.
- Ricote, M., Valledor, A.F., and Glass, C.K. (2004). Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arterioscler Thromb Vasc Biol. 24, 230-239.
- Saher, G., Brügger, B., Lappe-Siefke, C., Möbius, W., Tozawa, R.I., Wehr, M.C., Wieland, F., Ishibashi, S., and Nave, K.A. (2005). High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 8, 468-475.
- Saijo, K., Crotti, A., and Glass, C.K. (2013). Regulation of microglia activation and deactivation by nuclear receptors. Glia. 61, 104-111.
- Savage, J.C., Jay, T., Goduni, E., Quigley, C., Mariani, M.M., Malm, T., Ransohoff, R.M., Lamb, B.T., and Landreth, G.E. (2015). Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci. 35, 6532-6543.
- Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 8, 595-608.
- Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., and Rojas, J.C. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 549, 523-527.
- Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C.G., and Simons, K. (1998). Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 95, 6460-6464.
- Sinha, S. and Lieberburg, I. (1999). Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A. 96, 11049-11053.
- Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., and Roses, A.D. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 90, 1977-1981.
- Tai, L.M., Youmans, K.L., Jungbauer, L., Yu, C., and Ladu, M.J. (2011). Introducing human APOE into Aβ transgenic mouse models. Int J Alzheimers Dis. 2011.
- TCW, J., Liang, S.A., Qian, L., Pipalia, N.H., Chao, M.J., Shi, Y., Bertelsen, S.E., Kapoor, M., Marcora, E., and Sikora, E. (2019). Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. bioRxiv. 99, 713362.
- Tong, J., Borbat, P.P., Freed, J.H., and Shin, Y.K. (2009). A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol. Proc Natl Acad Sci U S A. 106, 5141-5146.
- Ulrich, J.D., Ulland, T.K., Mahan, T.E., Nyström, S., Nilsson, K.P., Song, W.M., Zhou, Y., Reinartz, M., Choi, S., and Jiang, H. (2018). ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 215, 1047-1058.
- van Deijk, A.F., Camargo, N., Timmerman, J., Heistek, T., Brouwers, J.F., Mogavero, F., Mansvelder, H.D., Smit, A.B., and Verheijen, M.H. (2017). Astrocyte lipid metabolism is critical for synapse development and function in vivo. Glia. 65, 670-682.
- Vance, J.E. (2012). Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech. 5, 746-755.
- Voskuhl, R.R., Itoh, N., Tassoni, A., Matsukawa, M.A., Ren, E., Tse, V., Jang, E., Suen, T.T., and Itoh, Y. (2019). Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci U S A. 116, 10130-10139.
- Wingo, T.S., Cutler, D.J., Wingo, A.P., Le, N.A., Rabinovici, G.D., Miller, B.L., Lah, J.J., and Levey, A.I. (2019). Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB. JAMA Neurol. 76, 809-817.
- Wood, W.G., Li, L., Müller, W.E., and Eckert, G.P. (2014). Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J Neurochem. 129, 559-572.
- Wu, L., Zhang, X., and Zhao, L. (2018). Human ApoE isoforms differentially modulate brain glucose and ketone body metabolism: implications for Alzheimer’s disease risk reduction and early intervention. J Neurosci. 38, 6665-6681.
- Wu, Y., Ma, Y., Liu, Z., Geng, Q., Chen, Z., and Zhang, Y. (2017). Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer’s disease mouse model. Neurosci Lett. 642, 102-106.
- Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R.W., and Huang, Y. (2006). Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 26, 4985-4994.
- Zhang, Y., Chen, K., Sloan, S.A., Bennett, M.L., Scholze, A.R., O’Keeffe, S., Phatnani, H.P., Guarnieri, P., Caneda, C., and Ruderisch, N. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 34, 11929-11947.
- Zhang, Y., Sloan, S.A., Clarke, L.E., Caneda, C., Plaza, C.A., Blumenthal, P.D., Vogel, H., Steinberg, G.K., Edwards, M.S.B., and Li, G. (2016). Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 89, 37-53.
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Mol. Cells 2019; 42(11): 739-746
Published online November 30, 2019 https://doi.org/10.14348/molcells.2019.0200
Copyright © The Korean Society for Molecular and Cellular Biology.
ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer’s Disease
Woojin Jeong, Hyein Lee, Sukhee Cho, and Jinsoo Seo*
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu 42988, Korea
Correspondence to:jsseo@dgist.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
Abstract
Significant knowledge about the pathophysiology of Alzheimer’s disease (AD) has been gained in the last century; however, the understanding of its causes of onset remains limited. Late-onset AD is observed in about 95% of patients, and
Keywords: Aβ, Alzheimer’s disease, ApoE4, apolipoprotein, cholesterol
INTRODUCTION
Alzheimer’s disease (AD), a progressive neurodegenerative disease, is one of the most common forms of irreversible dementia. Patients with AD suffer from cognitive impairment including language problems, mood changes, as well as memory loss. AD brains display amyloid-beta (Aβ) plaques, tau tangles, synaptic degradation, and neuronal loss. Among these neurobiological changes, Aβ plaque is considered to be one of the major hallmarks of AD because of its early appearance during the progression of the disease. Therefore, a major focus of ongoing research has been identifying the mechanisms of Aβ plaque formation and aggregation to target Aβ metabolism (O’Brien and Wong, 2011; Selkoe and Hardy, 2016). Although many studies and clinical trials for candidate drugs are currently underway, it is not yet clear how AD progresses, and no effective treatment for the disease exists. Currently-available drugs such as cholinesterase inhibitors only delay the onset of symptoms.
While early-onset AD pathology has been shown to be associated with genetic mutations in coding regions for proteins involved in Aβ metabolism (e.g., amyloid precursor protein;
ApoE is an apolipoprotein that plays a major role in cholesterol transport. In the brain, ApoE was previously believed to be mainly produced by astrocytes (Zhang et al., 2014; 2016). However, recent transcriptome analysis from human brain samples and hiPSC-derived brain cell types showed considerable expression of ApoE transcripts in microglia as well, and its expression is upregulated even in neurons in AD brains (Keren-Shaul et al., 2017; Lin et al., 2018; Mathys et al., 2019; Xu et al., 2006). There are three isoforms of ApoE; ApoE2, ApoE3, and ApoE4; only one or two amino acid variations differentiate these isoforms. ApoE3, the most common isoform present in about 78% of the population, has cysteine and arginine residues Cys112 and Arg158, whereas ApoE2 contains cysteine residues Cys112 and Cys158, and ApoE4 carries two arginine residues, Arg112 and Arg158. Although the difference is very subtle, it results in drastically differential effects on the risk for AD development. The allele frequency of ApoE2 is about 8%, and it is known to be neuroprotective. However, ApoE4 is one of the strongest risk factors for AD with a prevalence of about 14% (Liu et al., 2013; Strittmatter et al., 1993). Since its strong association with AD was first reported about twenty-five years ago (Corder et al., 1993; Strittmatter et al., 1993), many studies have been dedicated to determining how only one amino acid alteration in ApoE4 compared to ApoE3 could drastically increase the risk of AD (Liu et al., 2013).
In terms of the role of ApoE protein on Aβ metabolism, contradictory data have been reported in different studies. Some studies have reported a decrease in Aβ plaque in familial AD (fAD) mouse models with ApoE deficiency, while others showed that ApoE is required for Aβ reduction, including astrocyte-mediated Aβ clearance, and deletion of ApoE accelerated the accumulation of fibrillar amyloid in the brains of fAD mice (Bales et al., 1997; Holtzman et al., 1999; 2000; Kim et al., 2011; Koistinaho et al., 2004; Tai et al., 2011; Ulrich et al., 2018). Regarding the role of ApoE isoforms in AD pathogenesis, most studies agree that ApoE4 induces the highest Aβ accumulation and gliosis compared with other isoforms (Lin et al., 2018; Liu et al., 2013; 2017). Hyperphosphorylation of tau and related pathology (tauopathy), another hallmark of AD, has also been observed to be accelerated in the presence of the ApoE4 isoform (Shi et al., 2017). However, the mechanisms of ApoE4-induced AD pathogenesis still remain unclear.
Recent evidence has emerged showing abnormal cholesterol metabolism by ApoE4 could mediate AD-associated pathology. Here, we review recent research, providing some insights on how ApoE4-mediated cholesterol dysregulation could affect functions of different brain cell types in the context of AD.
NEURONS
Neurons are the most vulnerable to the toxicity of Aβ accumulation, and they are also the major cell type responsible for generating Aβ in the brain (Sinha and Lieberburg, 1999; Zhang et al., 2016). Various pathological features are induced by Aβ accumulation in neurons, such as synaptic degradation, altered synaptic and neuronal circuit activity, and cell death, which have been extensively reviewed elsewhere (Canter et al., 2016; De Strooper and Karran, 2016; Palop and Mucke, 2010; Selkoe and Hardy, 2016). In this review, we focus on how ApoE4-induced cholesterol metabolic abnormalities could affect Aβ generation and alter the synaptic function in neurons.
Neuronal lipid rafts provide the platform for APP to encounter its cleaving enzymes, resulting in Aβ generation. Cholesterol is one of the major components of lipid rafts, and its dysregulation affects Aβ production in neurons (Fassbender et al., 2001; Simons et al., 1998). Tethering of cholesterol to methyl-β-cyclodextrin (MβCD) enables its delivery to the plasma membrane, and neurons treated with MβCD-cholesterol complex show increased lipid raft formation and generation of Aβ (Cossec et al., 2010; Marquer et al., 2014). However, it remains unknown whether cholesterol-dependent facilitation of Aβ cleavage is through the regulation of β-secretase activity or/and increased formation of APP/β-secretase clusters (Kalvodova et al., 2005; Marquer et al., 2011). Some genetic variants associated with the LOAD are found on or near genes related to cholesterol transport such as
In the brain, cholesterol is mainly transmitted from astrocytes to neurons via lipoprotein particles, of which ApoE is one of the major components (Liu et al., 2013; Vance, 2012). ApoE, mainly produced by astrocytes, forms the lipoprotein complex with cholesterol and is secreted through the function of ABCAs. Among isoforms, ApoE4 displays lower transport affinity and binding capacity for lipids (Hatters et al., 2006; Vance, 2012), which could reduce cholesterol transport from astrocytes to neurons. As a result, the formation of neuronal lipid rafts and Aβ production might be affected by ApoE4 in the brain. Two recent studies with astrocytes generated from hiPSCs addressed this point, and both showed higher accumulation of cholesterol in ApoE4-expressing astrocytes than in isogenic ApoE3 astrocytes (Lin et al., 2018; TCW et al., 2019). However, regarding the secretion of cholesterol from these ApoE4 astrocytes, Lin et al. (2018) showed increased extracellular cholesterol levels by directly measuring secreted cholesterol in cultured media, while TCW et al. (2019) speculated that ApoE4 astrocytes might secrete less cholesterol due to a reduction of ApoE and Abca1, which mediate the efflux of cholesterol. Further studies are required to directly examine cholesterol transport to neurons from astrocytes with different ApoE isoforms.
Although cholesterol synthesis in neurons is lower than in astrocytes, particularly in adults (Nieweg et al., 2009; Pfrieger and Ungerer, 2011), ApoE isoform-dependent changes in cholesterol metabolism in neurons could also be driven in a cell-autonomous manner. For example, impaired efflux of cholesterol in ApoE4 neurons could contribute to its intracellular accumulation, leading to AD-related pathology, as observed in mice with cholesterol 24-hydroxylase-dependent cholesterol efflux suppressed in hippocampal neurons (Djelti et al., 2015). It is also important to investigate whether ApoE4 neurons have altered the expression and/or function of ApoE receptors such as those belonging to the low-density lipoprotein receptor family that can directly affect the uptake of extracellular cholesterol as well as Aβ clearance (Holtzman et al., 2012).
Cholesterol plays critical roles in synaptic function. It helps maintain adequate curvature of membrane to facilitate soluble NSF attachment protein receptor (SNARE)-mediated membrane fusion. Depleting cholesterol significantly reduces synaptic transmission, which can be reversed by reloading cholesterol (Linetti et al., 2010; Tong et al., 2009). Lack of cholesterol in neurons leads to impaired synaptic plasticity, evidenced by changes in paired-pulse facilitation and long-term potentiation (Koudinov and Koudinova, 2002). Hippocampal synapses in mice with decreased astrocytic cholesterol secretion also showed fewer synaptic vesicles, more immature synapses, and reduced expression of presynaptic synaptosomal nerve-associated protein 25 (SNAP-25) required for the exocytic release of neurotransmitters (van Deijk et al., 2017).
The role of ApoE isoforms on the formation of neuronal synapses and their function is not yet clear (Kim et al., 2014). A recent study with ApoE2, ApoE3 and ApoE4 knock-in (KI) mice in which the murine
ASTROCYTES
Lipoprotein-bound cholesterol from circulating plasma is prevented from entering the brain due to the presence of the blood-brain barrier (BBB), and astrocytes, which account for up to 40% of all brain cells in humans, are mainly responsible for producing cholesterol in the brain (Nieweg et al., 2009; Zhang et al., 2016). Cholesterol synthesis in astrocytes is tightly regulated by an internal feedback loop; if the intracellular level of cholesterol is low, cholesterol synthesis is induced by increasing proteolytic processes of sterol regulatory element-binding proteins (SREBPs) and reducing levels of proteins that mediate cholesterol efflux (Benarroch, 2008). When the intracellular cholesterol level is high, liver X receptor/retinoid X receptor (LXR/RXR)-mediated transcription for cholesterol transport proteins is increased, and efflux of lipoprotein complex is facilitated (Fig. 1). Cholesterol accumulation in ApoE4 astrocytes may not be due, solely, to impaired efflux resulting from reduced ApoE levels. Transcriptome analysis in hiPSC-derived astrocytes suggests the expression of genes involved in lipid metabolism is dysregulated in ApoE4 astrocytes, with an increase in the expression levels of cholesterol biosynthesis-related genes. Lysosomal cholesterol degradation processes also seem to be impaired in these cells (Lin et al., 2018; TCW et al., 2019). Further study is required to precisely elucidate the mechanisms underlying ApoE4-induced cholesterol accumulation in astrocytes, and how it can be targeted to resolve the abnormality.
Because cholesterol is a multifunctional metabolite, abnormal cholesterol metabolism by ApoE4 would lead not only altered cholesterol transport to other cell types but also functional deficits in astrocytes as observed in neurons (Fukui et al., 2015; Martín-Segura et al., 2019) and microglia (Churchward and Todd, 2014; Račková, 2013). However, there have not been many studies investigating the effects of intracellular cholesterol on cellular functions or formation of organelles in astrocytes. Therefore, investigating whether/how ApoE4 induces cholesterol-related cellular alterations in astrocytes are a priority. Cholesterol levels in astrocytes and glucose metabolism are closely linked (Ferris et al., 2017), A recent study showed ApoE isoform-dependent changes of brain glucose metabolism in mice (Wu et al., 2018), and it suggests that cholesterol abnormalities caused by ApoE4 could alter glucose metabolism (Fig. 1). Since astrocytes provide not only structural but metabolic supports for neurons, further investigations of astrocyte-specific changes in glucose metabolism in humanized ApoE KI mouse models or single-cell type culture systems with different ApoE isoforms, and its association with cholesterol dysregulation are needed.
MICROGLIA
The role of microglia in AD has been extensively investigated; nonetheless, their precise contribution to the development of AD pathology remains unclear. A recent development in single-cell transcriptome analysis technology revealed the spectrum of microglia phenotypes during AD pathogenesis and the species difference in transcriptomic information of disease-associated microglia between mice and humans (Keren-Shaul et al., 2017; Mathys et al., 2017; 2019). Although this topic is of great interest, it is beyond the scope of this review. Nevertheless, it is important to note that in both mouse and human cells, ApoE, along with triggering receptor expressed on myeloid cells 2 (TREM2), is shown to be upregulated and mediates microglial phenotypic changes and recruitment to amyloid plaques during the progression of AD (Cheng-Hathaway et al., 2018; Keren-Shaul et al., 2017; Parhizkar et al., 2019; Ulrich et al., 2018). Transition of microglia from resting (homeostatic) to reactive (disease-associated) phenotypes is generally mediated by transcriptional regulation (Deczkowska et al., 2018; Holtman et al., 2017; Krasemann et al., 2017). Although ApoE isoform-dependent transcriptional regulation was recently suggested by multiple studies (Huang et al., 2017; Lin et al., 2018; TCW et al., 2019), its precise mechanism is unclear.
Because excessive inflammatory response is associated with AD, the relationship between the level of cholesterol and immune responses in microglia, the brain resident macrophages, is of great interest. Interaction of cholesterol and inflammatory response in macrophages was suggested (Ricote et al., 2004). In microglia, however, regulation of inflammatory responses by peroxisome proliferator-activated receptor γ (PPARγ), LXR/RXR-mediated cholesterol synthesis, and phagocytic activity by PPARγ and LXR/RXR were reported in separate studies (Bernardo and Minghetti, 2006; Courtney and Landreth, 2016; Saijo et al., 2013; Savage et al., 2015). Direct interaction between cholesterol and inflammatory responses in this cell type has not been assessed.
The effect of microglial cholesterol on AD pathogenesis has been previously investigated using primary cultured cells. In primary microglia, accumulation of intracellular cholesterol induced by either MβCD-mediated loading or Niemann–Pick disease, type C1 (NPC1) inhibition (thus blocking cholesterol export from the lysosome) also increases intracellular Aβ. Furthermore, a negative correlation between cholesterol accumulation-induced intracellular Aβ and ApoE levels in these cells was observed. These data suggest that ApoE contributes to intracellular Aβ clearance through the regulation of cholesterol levels in microglia (Lee et al., 2012).
Recently developed protocols to generate microglia-like cells from hiPSC have enabled researchers to investigate functions and underlying mechanisms of ApoE4 variants in human microglia (Abud et al., 2017; Muffat et al., 2016; Pandya et al., 2017). Microglia-like cells from hiPSC carrying the
OLIGODENDROCYTES
Oligodendrocytes have a unique structure called myelin that ensheathes axons, facilitating conduction of action potentials and protecting neurons from other possible extracellular insults (Domingues et al., 2016). Lipids are the major components of myelin membranes, consisting of at least 70% of their dry weight, whereas membranes in other cell types are generally composed of about 30% lipids and 70% proteins (Chrast et al., 2011; Ingólfsson et al., 2017). This suggests that altered lipid composition by abnormal metabolic processes would affect not only intracellular compartments generally seen in other cell types but also the formation and function of myelin, which is critical for neuronal function.
Among lipid metabolites in myelin membranes, cholesterol has been shown to have a significant role in myelin formation. Inhibition of cholesterol-synthesizing ability in oligodendrocytes by deleting squalene synthases leads to a significant reduction of myelination in oligodendrocytes, inducing behavioral abnormalities such as ataxia and tremors in mice (Saher et al., 2005). Increased levels of gene expression associated with cholesterol biosynthesis were also observed in oligodendrocyte lineage cells during the remyelination phase following axonal damage (Voskuhl et al., 2019). These data demonstrate the major contribution of oligodendrocyte-derived cholesterol for myelination in the brain. A recent study also reported the role of astrocytic cholesterol in the formation of myelin following axonal injury (Camargo et al., 2017). In this study, cell type-specific deletion of SREBP cleavage-activating protein (SCAP), which mediates cholesterol synthesis, either in oligodendrocytes or astrocytes, showed only partial impairment of myelination in mice. When SCAP is ablated in both cell types, however, mice showed an almost complete absence of myelination in the brain. These results suggest that altered levels of extracellular and intracellular cholesterol for oligodendrocytes could regulate myelination in the brain.
As a major cholesterol transporter, it would not be surprising that ApoE is involved in myelination processes. Indeed, a recent study showed that ApoE is required for cholesterol clearance in demyelinating lesions to prevent lysosomal accumulation of myelin debris (Cantuti-Castelvetri et al., 2018). Studies have found an association between amyloid pathology with myelin alteration in AD animal models and preclinical studies, including a reduction of myelination associated with brain atrophy (Dean et al., 2017; Wu et al., 2017). Further work is needed to determine the differential role of ApoE isoforms in oligodendrocytes and whether and how ApoE4-associated cholesterol dysregulation in these cells drive AD-associated pathology.
CONCLUSION
Investigating pathological features of whole AD brain samples would be of interest. However, it is also necessary to tease out cell type-specific alterations and their contributions to AD pathogenesis. Recent investigations of cell type-specific functions of ApoE4 from various brain cell types isolated from ApoE KI mice or derived from hiPSC showed impaired cholesterol metabolism by ApoE4, specifically in glial cells that were not evident from previous studies that relied on bulk brain samples composed of mixed cell populations (Lin et al., 2018; Nuriel et al., 2017; TCW et al., 2019). As we reviewed, cholesterol metabolism is closely linked to various functions in different types of cells in the brain, and its dysregulation can lead to AD-associated pathological phenotypes in each cell type, including Aβ upregulation in neurons, abnormal glucose metabolism in astrocytes, inflammatory responses in microglia, and myelination defects in oligodendrocytes (Fig. 2).
In addition to these cell types, the BBB, which is composed of various cell types, including pericytes and endothelial cells, was also shown to be influenced by ApoE4. Multiple studies suggest that ApoE4 leads to BBB leakage through the degeneration of pericytes and the disruption of the integrity of tight junctions (Casey et al., 2015; Nishitsuji et al., 2011), which leads to the accumulation of serum proteins in the brain (Bell et al., 2012). This can result in further elevation of brain cholesterol. It is also possible that increased cholesterol in the brain or plasma by ApoE4 affects BBB integrity and may lead to leakage (Jiang et al., 2012; Kalayci et al., 2009). While there is a close coupling between neurovascular dysfunction and AD, the cell types mentioned above are understudied in the context of AD. Exploring detailed mechanisms in BBB pathogenesis in ApoE4 brain may provide insights into a new therapeutic avenue.
While we largely discuss ApoE4 as an AD risk factor in terms of cholesterol metabolism in the brain, it is also important to mention that in several studies it has been suggested that plasma cholesterol level and AD risk/pathology are linked (Pappolla et al., 2003; Wingo et al., 2019). Epidemiological studies show an increased concentration of plasma cholesterol in AD patients (Wood et al., 2014), and diet-induced hypercholesterolemia in AD mouse models leads to increased Aβ and impaired memory (Park et al., 2013). Unlike physiological conditions in which the translocation of peripheral cholesterol to the brain is limited, it is facilitated when leakage of the BBB occurs under pathological conditions. Although more studies are necessary to identify plasma cholesterol as a causative factor, it is important to understand the dynamic relationship between brain cholesterol and plasma cholesterol in terms of AD pathogenesis.
Further studies are also required to determine whether other AD genetic risk factors associated with cholesterol homeostasis, including Clustrin (apolipoprotein J) and
ACKNOWLEDGMENTS
This work was supported by DGIST MIREBraiN program and the National Research Foundation of Korea (NRF) grants (2018M3C7A1056275). We thank Joonho Cho for careful reading of the manuscript and helpful comments.
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References
- Abud, E.M., Ramirez, R.N., Martinez, E.S., Healy, L.M., Nguyen, C.H.H., Newman, S.A., Yeromin, A.V., Scarfone, V.M., Marsh, S.E., and Fimbres, C. (2017). iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 94, 278-293.e9.
- Baik, S.H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.I., and Mook-Jung, I. (2019). A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 30, 493-507.e6.
- Bales, K.R., Verina, T., Dodel, R.C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E.M., Little, S.P., and Cummins, D.J. (1997). Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 17, 263-264.
- Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M., Betsholtz, C., Armulik, A., and Sallstrom, J. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 485, 512-516.
- Benarroch, E.E. (2008). Brain cholesterol metabolism and neurologic disease. Neurology. 71, 1368-1373.
- Bernardo, A. and Minghetti, L. (2006). PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr Pharm Des. 12, 93-109.
- Camargo, N., Goudriaan, A., van Deijk, A.L.F., Otte, W.M., Brouwers, J.F., Lodder, H., Gutmann, D.H., Nave, K.A., Dijkhuizen, R.M., and Mansvelder, H.D. (2017). Oligodendroglial myelination requires astrocyte-derived lipids. PLoS Biol. 15, e1002605.
- Canter, R.G., Penney, J., and Tsai, L.H. (2016). The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature. 539, 187-196.
- Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.T., Su, M., Sen, P., Ruhwedel, T., Mitkovski, M., Trendelenburg, G., and Lütjohann, D. (2018). Defective cholesterol clearance limits remyelination in the aged central nervous system. Science. 359, 684-688.
- Casey, C.S., Atagi, Y., Yamazaki, Y., Shinohara, M., Tachibana, M., Fu, Y., Bu, G., and Kanekiyo, T. (2015). Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA protein-mediated pathway. J Biol Chem. 290, 14208-14217.
- Cheng-Hathaway, P.J., Reed-Geaghan, E.G., Jay, T.R., Casali, B.T., Bemiller, S.M., Puntambekar, S.S., von Saucken, V.E., Williams, R.Y., Karlo, J.C., and Moutinho, M. (2018). The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer’s disease. Mol Neurodegener. 13, 29.
- Chrast, R., Saher, G., Nave, K.A., and Verheijen, M.H.G. (2011). Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res. 52, 419-434.
- Chu, C.S., Tseng, P.T., Stubbs, B., Chen, T.Y., Tang, C.H., Li, D.J., Yang, W.C., Chen, Y.W., Wu, C.K., and Veronese, N. (2018). Use of statins and the risk of dementia and mild cognitive impairment: a systematic review and meta-analysis. Sci Rep. 8, 5804.
- Chung, W.S., Verghese, P.B., Chakraborty, C., Joung, J., Hyman, B.T., Ulrich, J.D., Holtzman, D.M., and Barres, B.A. (2016). Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 113, 10186-10191.
- Churchward, M.A. and Todd, K.G. (2014). Statin treatment affects cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms. Mol Brain. 7, 85.
- Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., and Pericak-Vance, M.A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 261, 921-923.
- Cossec, J.C., Simon, A., Marquer, C., Moldrich, R.X., Leterrier, C., Rossier, J., Duyckaerts, C., Lenkei, Z., and Potier, M.C. (2010). Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta. 1801, 846-852.
- Courtney, R. and Landreth, G.E. (2016). LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol Metab. 27, 404-414.
- De Strooper, B. and Karran, E. (2016). The cellular phase of Alzheimer’s disease. Cell. 164, 603-615.
- Dean, D.C., Hurley, S.A., Kecskemeti, S.R., O’Grady, J.P., Canda, C., Davenport-Sis, N.J., Carlsson, C.M., Zetterberg, H., Blennow, K., and Asthana, S. (2017). Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 74, 41-49.
- Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., and Amit, I. (2018). Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 173, 1073-1081.
- Di Paolo, G. and Kim, T.W. (2011). Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci. 12, 284-296.
- Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bièche, I., Marquer, C., Chali, F., Ayciriex, S., and Auzeil, N. (2015). CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease. Brain. 138, 2383-2398.
- Domingues, H.S., Portugal, C.C., Socodato, R., and Relvas, J.B. (2016). Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol. 4, 71.
- Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., and von Bergmann, K. (2001). Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 98, 5856-5861.
- Ferris, H.A., Perry, R.J., Moreira, G.V., Shulman, G.I., Horton, J.D., and Kahn, C.R. (2017). Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A. 114, 1189-1194.
- Fukui, K., Ferris, H.A., and Kahn, C.R. (2015). Effect of cholesterol reduction on receptor signaling in neurons. J Biol Chem. 290, 26383-26392.
- Hatters, D.M., Peters-Libeu, C.A., and Weisgraber, K.H. (2006). Apolipoprotein E structure: insights into function. Trends Biochem Sci. 31, 445-454.
- Holtman, I.R., Skola, D., and Glass, C.K. (2017). Transcriptional control of microglia phenotypes in health and disease. J Clin Invest. 127, 3220-3229.
- Holtzman, D.M., Bales, K.R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A.M., Chang, L.K., Sun, Y., and Paul, S.M. (1999). Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J Clin Invest. 103, R15-R21.
- Holtzman, D.M., Fagan, A.M., Mackey, B., Tenkova, T., Sartorius, L., Paul, S.M., Bales, K., Ashe, K.H., Irizarry, M.C., and Hyman, B.T. (2000). Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol. 47, 739-747.
- Holtzman, D.M., Herz, J., and Bu, G. (2012). Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. 2, a006312.
- Huang, Y.W.A., Zhou, B., Wernig, M., and Südhof, T.C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. 168, 427-441.e21.
- Ingólfsson, H.I., Carpenter, T.S., Bhatia, H., Bremer, P.T., Marrink, S.J., and Lightstone, F.C. (2017). Computational lipidomics of the neuronal plasma membrane. Biophys J. 113, 2271-2280.
- Jiang, X., Guo, M., Su, J., Lu, B., Ma, D., Zhang, R., Yang, L., Wang, Q., Ma, Y., and Fan, Y. (2012). Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. Int J Alzheimers Dis. 2012, 109324-109327.
- Kalayci, R., Kaya, M., Uzun, H., Bilgic, B., Ahishali, B., Arican, N., Elmas, I., and Küçük, M. (2009). Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats. Int J Neurosci. 119, 1881-1904.
- Kalvodova, L., Kahya, N., Schwille, P., Ehehalt, R., Verkade, P., Drechsel, D., and Simons, K. (2005). Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J Biol Chem. 280, 36815-36823.
- Karch, C.M. and Goate, A.M. (2015). Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 77, 43-51.
- Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D., and Toth, B. (2017). A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 169, 1276-1290.e17.
- Kim, J., Jiang, H., Park, S., Eltorai, A.E.M., Stewart, F.R., Yoon, H., Basak, J.M., Finn, M.B., and Holtzman, D.M. (2011). Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci. 31, 18007-18012.
- Kim, J., Yoon, H., Basak, J., and Kim, J. (2014). Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cells. 37, 767-776.
- Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., and Bales, K.R. (2004). Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 10, 719-726.
- Koudinov, A.R. and Koudinova, N.V. (2002). Cholesterol’s role in synapse formation. Science. 295, 2213.
- Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., and Fanek, Z. (2017). The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 47, 566-581.e9.
- Kunkle, B.W., Grenier-Boley, B., Sims, R., Bis, J.C., Damotte, V., Naj, A.C., Boland, A., Vronskaya, M., van der Lee, S.J., and Amlie-Wolf, A. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 51, 414-430.
- Lambert, J.C., Ibrahim-Verbaas, C.A., Harold, D., Naj, A.C., Sims, R., Bellenguez, C., DeStafano, A.L., Bis, J.C., Beecham, G.W., and Grenier-Boley, B. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 45, 1452-1458.
- Lee, C.Y.D., Tse, W., Smith, J.D., and Landreth, G.E. (2012). Apolipoprotein E promotes β-amyloid trafficking and degradation by modulating microglial cholesterol levels. J Biol Chem. 287, 2032-2044.
- Li, Y., Liu, Q., Sun, J., Wang, J., Liu, X., and Gao, J. (2018). Mitochondrial protective mechanism of simvastatin protects against amyloid β peptide-induced injury in SH-SY5Y cells. Int J Mol Med. 41, 2997-3005.
- Lin, Y.T., Seo, J., Gao, F., Feldman, H.M., Wen, H.L., Penney, J., Cam, H.P., Gjoneska, E., Raja, W.K., and Cheng, J. (2018). APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 98, 1141-1154.e7.
- Linetti, A., Fratangeli, A., Taverna, E., Valnegri, P., Francolini, M., Cappello, V., Matteoli, M., Passafaro, M., and Rosa, P. (2010). Cholesterol reduction impairs exocytosis of synaptic vesicles. J Cell Sci. 123, 595-605.
- Liu, C.C., Liu, C.C., Kanekiyo, T., Xu, H., and Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 9, 106-118.
- Liu, C.C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.W., and Bu, G. (2017). ApoE4 accelerates early seeding of amyloid pathology. Neuron. 96, 1024-1032.e3.
- Marquer, C., Devauges, V., Cossec, J.C., Liot, G., Lécart, S., Saudou, F., Duyckaerts, C., Lévêque-Fort, S., and Potier, M.C. (2011). Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J. 25, 1295-1305.
- Marquer, C., Laine, J., Dauphinot, L., Hanbouch, L., Lemercier-Neuillet, C., Pierrot, N., Bossers, K., Le, M., Corlier, F., and Benstaali, C. (2014). Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes. Mol Neurodegener. 9, 60.
- Martín-Segura, A., Ahmed, T., Casadomé-Perales, Á, Palomares-Perez, I., Palomer, E., Kerstens, A., Munck, S., Balschun, D., and Dotti, C.G. (2019). Age-associated cholesterol reduction triggers brain insulin resistance by facilitating ligand-independent receptor activation and pathway desensitization. Aging Cell. 18, e12932.
- Mathys, H., Adaikkan, C., Gao, F., Young, J.Z., Manet, E., Hemberg, M., De Jager, P.L., Ransohoff, R.M., Regev, A., and Tsai, L.H. (2017). Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366-380.
- Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J.Z., Menon, M., He, L., Abdurrob, F., and Jiang, X. (2019). Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 570, 332-337.
- Muffat, J., Li, Y., Yuan, B., Mitalipova, M., Omer, A., Corcoran, S., Bakiasi, G., Tsai, L.H., Aubourg, P., and Ransohoff, R.M. (2016). Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 22, 1358-1367.
- Nieweg, K., Schaller, H., and Pfrieger, F.W. (2009). Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J Neurochem. 109, 125-134.
- Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., and Michikawa, M. (2011). Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem. 286, 17536-17542.
- Nuriel, T., Angulo, S.L., Khan, U., Ashok, A., Chen, Q., Figueroa, H.Y., Emrani, S., Liu, L., Herman, M., and Barrett, G. (2017). Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nat Commun. 8, 1464.
- O’Brien, R.J. and Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 34, 185-204.
- Palop, J.J. and Mucke, L. (2010). Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 13, 812-818.
- Pandya, H., Shen, M.J., Ichikawa, D.M., Sedlock, A.B., Choi, Y., Johnson, K.R., Kim, G., Brown, M.A., Elkahloun, A.G., and Maric, D. (2017). Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 20, 753-759.
- Pappolla, M.A., Bryant-Thomas, T.K., Herbert, D., Pacheco, J., Fabra Garcia, M., Manjon, M., Girones, X., Henry, T.L., Matsubara, E., and Zambon, D. (2003). Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology. 61, 199-205.
- Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., and Katzmarski, N. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 22, 191-204.
- Park, S.H., Kim, J.H., Choi, K.H., Jang, Y.J., Bae, S.S., Choi, B.T., and Shin, H.K. (2013). Hypercholesterolemia accelerates amyloid β-induced cognitive deficits. Int J Mol Med. 31, 577-582.
- Pfrieger, F.W. and Ungerer, N. (2011). Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res. 50, 357-371.
- Račková, L. (2013). Cholesterol load of microglia: contribution of membrane architecture changes to neurotoxic power?. Arch Biochem Biophys. 537, 91-103.
- Ricote, M., Valledor, A.F., and Glass, C.K. (2004). Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arterioscler Thromb Vasc Biol. 24, 230-239.
- Saher, G., Brügger, B., Lappe-Siefke, C., Möbius, W., Tozawa, R.I., Wehr, M.C., Wieland, F., Ishibashi, S., and Nave, K.A. (2005). High cholesterol level is essential for myelin membrane growth. Nat Neurosci. 8, 468-475.
- Saijo, K., Crotti, A., and Glass, C.K. (2013). Regulation of microglia activation and deactivation by nuclear receptors. Glia. 61, 104-111.
- Savage, J.C., Jay, T., Goduni, E., Quigley, C., Mariani, M.M., Malm, T., Ransohoff, R.M., Lamb, B.T., and Landreth, G.E. (2015). Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci. 35, 6532-6543.
- Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 8, 595-608.
- Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., and Rojas, J.C. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 549, 523-527.
- Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C.G., and Simons, K. (1998). Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 95, 6460-6464.
- Sinha, S. and Lieberburg, I. (1999). Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A. 96, 11049-11053.
- Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., and Roses, A.D. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 90, 1977-1981.
- Tai, L.M., Youmans, K.L., Jungbauer, L., Yu, C., and Ladu, M.J. (2011). Introducing human APOE into Aβ transgenic mouse models. Int J Alzheimers Dis. 2011.
- TCW, J., Liang, S.A., Qian, L., Pipalia, N.H., Chao, M.J., Shi, Y., Bertelsen, S.E., Kapoor, M., Marcora, E., and Sikora, E. (2019). Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. bioRxiv. 99, 713362.
- Tong, J., Borbat, P.P., Freed, J.H., and Shin, Y.K. (2009). A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol. Proc Natl Acad Sci U S A. 106, 5141-5146.
- Ulrich, J.D., Ulland, T.K., Mahan, T.E., Nyström, S., Nilsson, K.P., Song, W.M., Zhou, Y., Reinartz, M., Choi, S., and Jiang, H. (2018). ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med. 215, 1047-1058.
- van Deijk, A.F., Camargo, N., Timmerman, J., Heistek, T., Brouwers, J.F., Mogavero, F., Mansvelder, H.D., Smit, A.B., and Verheijen, M.H. (2017). Astrocyte lipid metabolism is critical for synapse development and function in vivo. Glia. 65, 670-682.
- Vance, J.E. (2012). Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech. 5, 746-755.
- Voskuhl, R.R., Itoh, N., Tassoni, A., Matsukawa, M.A., Ren, E., Tse, V., Jang, E., Suen, T.T., and Itoh, Y. (2019). Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci U S A. 116, 10130-10139.
- Wingo, T.S., Cutler, D.J., Wingo, A.P., Le, N.A., Rabinovici, G.D., Miller, B.L., Lah, J.J., and Levey, A.I. (2019). Association of early-onset Alzheimer disease with elevated low-density lipoprotein cholesterol levels and rare genetic coding variants of APOB. JAMA Neurol. 76, 809-817.
- Wood, W.G., Li, L., Müller, W.E., and Eckert, G.P. (2014). Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J Neurochem. 129, 559-572.
- Wu, L., Zhang, X., and Zhao, L. (2018). Human ApoE isoforms differentially modulate brain glucose and ketone body metabolism: implications for Alzheimer’s disease risk reduction and early intervention. J Neurosci. 38, 6665-6681.
- Wu, Y., Ma, Y., Liu, Z., Geng, Q., Chen, Z., and Zhang, Y. (2017). Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer’s disease mouse model. Neurosci Lett. 642, 102-106.
- Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R.W., and Huang, Y. (2006). Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 26, 4985-4994.
- Zhang, Y., Chen, K., Sloan, S.A., Bennett, M.L., Scholze, A.R., O’Keeffe, S., Phatnani, H.P., Guarnieri, P., Caneda, C., and Ruderisch, N. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 34, 11929-11947.
- Zhang, Y., Sloan, S.A., Clarke, L.E., Caneda, C., Plaza, C.A., Blumenthal, P.D., Vogel, H., Steinberg, G.K., Edwards, M.S.B., and Li, G. (2016). Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 89, 37-53.
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