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http://dx.doi.org/10.14348/molcells.2019.0200

ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer's Disease  

Jeong, Woojin (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Lee, Hyein (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Cho, Sukhee (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Seo, Jinsoo (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology (DGIST))
Publication Information
Molecules and Cells / v.42, no.11, 2019 , pp. 739-746 More about this Journal
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 APOE4-encoding apolipoprotein E4 (ApoE4) is strongly associated with these cases. As an apolipoprotein, the function of ApoE in brain cholesterol transport has been extensively studied and widely appreciated. Development of new technologies such as human-induced pluripotent stem cells (hiPSCs) and CRISPR-Cas9 genome editing tools have enabled us to develop human brain model systems in vitro and readily manipulate genomic information. In the context of these advances, recent studies provide strong evidence that abnormal cholesterol metabolism by ApoE4 could be linked to AD-associated pathology. In this review, we discuss novel discoveries in brain cholesterol dysregulation by ApoE4. We further elaborate cell type-specific roles in cholesterol regulation of four major brain cell types, neurons, astrocytes, microglia, and oligodendrocytes, and how its dysregulation can be linked to AD pathology.
Keywords
$A{\beta}$; Alzheimer's disease; ApoE4; apolipoprotein; cholesterol;
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1 Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191-204.   DOI
2 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 ${\beta}$-induced cognitive deficits. Int. J. Mol. Med. 31, 577-582.   DOI
3 Pfrieger, F.W. and Ungerer, N. (2011). Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357-371.   DOI
4 Bernardo, A. and Minghetti, L. (2006). PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr. Pharm. Des. 12, 93-109.   DOI
5 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., Mansvelder, H.D., et al. (2017). Oligodendroglial myelination requires astrocyte-derived lipids. PLoS Biol. 15, e1002605.   DOI
6 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.   DOI
7 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.   DOI
8 Cantuti-Castelvetri, L., Fitzner, D., Bosch-Queralt, M., Weil, M.T., Su, M., Sen, P., Ruhwedel, T., Mitkovski, M., Trendelenburg, G., Lutjohann, D., et al. (2018). Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359, 684-688.   DOI
9 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.   DOI
10 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., Moutinho, M., et al. (2018). The Trem2 R47H variant confers loss-offunction-like phenotypes in Alzheimer's disease. Mol. Neurodegener. 13, 29.   DOI
11 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., Veronese, N., et al. (2018). Use of statins and the risk of dementia and mild cognitive impairment: a systematic review and meta-analysis. Sci. Rep. 8, 5804.   DOI
12 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.   DOI
13 Wood, W.G., Li, L., Muller, W.E., and Eckert, G.P. (2014). Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. J. Neurochem. 129, 559-572.   DOI
14 Zhang, Y., Chen, K., Sloan, S.A., Bennett, M.L., Scholze, A.R., O'Keeffe, S., Phatnani, H.P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929-11947.   DOI
15 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.   DOI
16 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.   DOI
17 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.   DOI
18 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., Li, G., et al. (2016). Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37-53.   DOI
19 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.   DOI
20 Rackova, L. (2013). Cholesterol load of microglia: contribution of membrane architecture changes to neurotoxic power? Arch. Biochem. Biophys. 537, 91-103.   DOI
21 Saher, G., Brugger, 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.   DOI
22 Saijo, K., Crotti, A., and Glass, C.K. (2013). Regulation of microglia activation and deactivation by nuclear receptors. Glia 61, 104-111.   DOI
23 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.   DOI
24 Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8, 595-608.   DOI
25 Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., Rojas, J.C., et al. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523-527.   DOI
26 Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C.G., and Simons, K. (1998). Cholesterol depletion inhibits the generation of betaamyloid in hippocampal neurons. Proc. Natl. Acad. Sci. U. S. A. 95, 6460-6464.   DOI
27 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.   DOI
28 Sinha, S. and Lieberburg, I. (1999). Cellular mechanisms of beta-amyloid production and secretion. Proc. Natl. Acad. Sci. U. S. A. 96, 11049-11053.   DOI
29 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.   DOI
30 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.   DOI
31 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 $A{\beta}$ secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim. Biophys. Acta 1801, 846-852.   DOI
32 Courtney, R. and Landreth, G.E. (2016). LXR regulation of brain cholesterol: from development to disease. Trends Endocrinol. Metab. 27, 404-414.   DOI
33 De Strooper, B. and Karran, E. (2016). The cellular phase of Alzheimer's disease. Cell 164, 603-615.   DOI
34 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., Asthana, S., et al. (2017). Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol. 74, 41-49.   DOI
35 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.   DOI
36 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.   DOI
37 Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S., and Roses, A.D. (1993). Apolipoprotein E: highavidity 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.   DOI
38 Tai, L.M., Youmans, K.L., Jungbauer, L., Yu, C., and Ladu, M.J. (2011). Introducing human APOE into $A{\beta}$ transgenic mouse models. Int. J. Alzheimers Dis. 2011, 810981.
39 TCW, J., Liang, S.A., Qian, L., Pipalia, N.H., Chao, M.J., Shi, Y., Bertelsen, S.E., Kapoor, M., Marcora, E., Sikora, E., et al. (2019). Cholesterol and matrisome pathways dysregulated in human APOE ${\varepsilon}4$ glia. bioRxiv 99, 713362.
40 Ulrich, J.D., Ulland, T.K., Mahan, T.E., Nyström, S., Nilsson, K.P., Song, W.M., Zhou, Y., Reinartz, M., Choi, S., Jiang, H., et al. (2018). ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047-1058.   DOI
41 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.   DOI
42 Vance, J.E. (2012). Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis. Model Mech. 5, 746-755.   DOI
43 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.   DOI
44 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.   DOI
45 Di Paolo, G. and Kim, T.W. (2011). Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284-296.   DOI
46 Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bieche, I., Marquer, C., Chali, F., Ayciriex, S., Auzeil, N., et al. (2015). CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease. Brain 138, 2383-2398.   DOI
47 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.
48 Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., von Bergmann, K., et al. (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.   DOI
49 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.   DOI
50 Hatters, D.M., Peters-Libeu, C.A., and Weisgraber, K.H. (2006). Apolipoprotein E structure: insights into function. Trends Biochem. Sci. 31, 445-454.   DOI
51 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.   DOI
52 Lin, Y.T., Seo, J., Gao, F., Feldman, H.M., Wen, H.L., Penney, J., Cam, H.P., Gjoneska, E., Raja, W.K., Cheng, J., et al. (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.   DOI
53 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., Grenier-Boley, B., et al. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452-1458.   DOI
54 Lee, C.Y.D., Tse, W., Smith, J.D., and Landreth, G.E. (2012). Apolipoprotein E promotes ${\beta}$-amyloid trafficking and degradation by modulating microglial cholesterol levels. J. Biol. Chem. 287, 2032-2044.   DOI
55 Li, Y., Liu, Q., Sun, J., Wang, J., Liu, X., and Gao, J. (2018). Mitochondrial protective mechanism of simvastatin protects against amyloid ${\beta}$ peptideinduced injury in SH-SY5Y cells. Int. J. Mol. Med. 41, 2997-3005.
56 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.   DOI
57 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.   DOI
58 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.   DOI
59 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.   DOI
60 Marquer, C., Devauges, V., Cossec, J.C., Liot, G., Lecart, S., Saudou, F., Duyckaerts, C., Leveque-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.   DOI
61 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.   DOI
62 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.   DOI
63 Huang, Y.W.A., Zhou, B., Wernig, M., and Sudhof, T.C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and $A{\beta}$ secretion. Cell 168, 427-441.e21.   DOI
64 Ingolfsson, 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.   DOI
65 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.
66 Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J.Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019). Single-cell transcriptomic analysis of Alzheimer's disease. Nature 570, 332-337.   DOI
67 Marquer, C., Laine, J., Dauphinot, L., Hanbouch, L., Lemercier-Neuillet, C., Pierrot, N., Bossers, K., Le, M., Corlier, F., Benstaali, C., et al. (2014). Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer's disease early phenotypes. Mol. Neurodegener. 9, 60.   DOI
68 Martin-Segura, A., Ahmed, T., Casadome-Perales, A., 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.   DOI
69 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.   DOI
70 Muffat, J., Li, Y., Yuan, B., Mitalipova, M., Omer, A., Corcoran, S., Bakiasi, G., Tsai, L.H., Aubourg, P., Ransohoff, R.M., et al. (2016). Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358-1367.   DOI
71 Karch, C.M. and Goate, A.M. (2015). Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43-51.   DOI
72 Kalayci, R., Kaya, M., Uzun, H., Bilgic, B., Ahishali, B., Arican, N., Elmas, I., and Kucuk, M. (2009). Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats. Int. J. Neurosci. 119, 1881-1904.   DOI
73 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.   DOI
74 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.   DOI
75 Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., and Michikawa, M. (2011). Apolipoprotein E regulates the integrity of tight junctions in an isoformdependent manner in an in vitro blood-brain barrier model. J. Biol. Chem. 286, 17536-17542.   DOI
76 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., Fimbres, C., et al. (2017). iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278-293.e9.   DOI
77 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.   DOI
78 Bales, K.R., Verina, T., Dodel, R.C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E.M., Little, S.P., Cummins, D.J., et al. (1997). Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263-264.   DOI
79 Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516.   DOI
80 Benarroch, E.E. (2008). Brain cholesterol metabolism and neurologic disease. Neurology 71, 1368-1373.   DOI
81 Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017). A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169, 1276-1290.e17.   DOI
82 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-${\beta}$ amyloidosis. J. Neurosci. 31, 18007-18012.   DOI
83 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.   DOI
84 Pandya, H., Shen, M.J., Ichikawa, D.M., Sedlock, A.B., Choi, Y., Johnson, K.R., Kim, G., Brown, M.A., Elkahloun, A.G., Maric, D., et al. (2017). Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753-759.   DOI
85 Nuriel, T., Angulo, S.L., Khan, U., Ashok, A., Chen, Q., Figueroa, H.Y., Emrani, S., Liu, L., Herman, M., Barrett, G., et al. (2017). Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology. Nat. Commun. 8, 1464.   DOI
86 O'Brien, R.J. and Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer's disease. Annu. Rev. Neurosci. 34, 185-204.   DOI
87 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.   DOI
88 Pappolla, M.A., Bryant-Thomas, T.K., Herbert, D., Pacheco, J., Fabra Garcia, M., Manjon, M., Girones, X., Henry, T.L., Matsubara, E., Zambon, D., et al. (2003). Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61, 199-205.   DOI
89 Koudinov, A.R. and Koudinova, N.V. (2002). Cholesterol's role in synapse formation. Science 295, 2213.   DOI
90 Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K.R., et al. (2004). Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat. Med. 10, 719-726.   DOI
91 Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O'Loughlin, E., Xu, Y., Fanek, Z., et al. (2017). The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566-581.e9.   DOI
92 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., Amlie-Wolf, A., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates $A{\beta}$, tau, immunity and lipid processing. Nat. Genet. 51, 414-430.   DOI