Oxidized cholesterol as the driving force behind the development of Alzheimer's disease

Frontiers in Aging Neuroscience

Volumn 7, Issue JUN, 2015, Pages

  Gamba, Paola ^a   Testa, Gabriella ^a   Gargiulo, Simona ^a   Staurenghi, Erica ^a   Poli, Giuseppe ^a   Leonarduzzi, Gabriella ^a  

^a UNIVERSITY OF TURIN   (Italy)

Author keywords

Alzheimer's disease; Inflammation; Oxidative stress; Oxidized cholesterol; Oxysterols

Indexed keywords

26 HYDROXYCHOLESTEROL; ABC TRANSPORTER A1; ABC TRANSPORTER G1; AMYLOID BETA PROTEIN; BETA SECRETASE 1; CD36 ANTIGEN; CD47 ANTIGEN; CHOLESTEROL; COLECALCIFEROL 24 HYDROXYLASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; OXYSTEROL; PRESENILIN 1; PRESENILIN 2; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; SECALCIFEROL; TOLL LIKE RECEPTOR; VERY LATE ACTIVATION ANTIGEN 1;

ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; CELL DEATH; CHOLESTEROL METABOLISM; COGNITIVE DEFECT; CYTOKINE PRODUCTION; DEGENERATIVE DISEASE; DEMENTIA; DISEASE COURSE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA POLYMORPHISM; HUMAN; HYPERCHOLESTEROLEMIA; INFLAMMATION; LIPID PEROXIDATION; LIPID RAFT; NERVOUS SYSTEM INFLAMMATION; NEUROFIBRILLARY TANGLE; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PATHOPHYSIOLOGY; PROTEIN AGGREGATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REVIEW;

EID: 84936097545     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2015.00119     Document Type: Review

References (292)

1. Abbas, N., Bednar, I., Mix, E., Marie, S., Paterson, D., Ljungberg, A., et al. (2002). Up-regulation of the inflammatory cytokines IFN-gamma and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APP(SWE) transgenic mice. J. Neuroimmunol. 126, 50-57. doi: 10.1016/s0165-5728(02)00050-4
2. Abildayeva, K., Jansen, P. J., Hirsch-Reinshagen, V., Bloks, V. W., Bakker, A. H., Ramaekers, F. C., et al. (2006). 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J. Biol. Chem. 281, 12799-12808. doi: 10.1074/jbc.m601019200
3. Acarin, L., González, B., and Castellano, B. (2000). Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur. J. Neurosci. 12, 3505-3520. doi: 10.1046/j.1460-9568.2000.00226.x
4. Ahonen, L., Maire, F. B., Savolainen, M., Kopra, J., Vreeken, R. J., Hankemeier, T., et al. (2014). Analysis of oxysterols and vitamin D metabolites in mouse brain and cell line samples by ultra-high-performance liquid chromatography-atmospheric pressure photoionization-mass spectrometry. J. Chromatogr. A. 1364, 214-222. doi: 10.1016/j.chroma.2014.08.088
5. Anandatheerthavarada, H. K., Biswas, G., Robin, M. A., and Avadhani, N. G. (2003). Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell. Biol. 161, 41-54. doi: 10.1083/jcb.200207030
6. Ansari, M. A., and Scheff, S. W. (2010). Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J. Neuropathol. Exp. Neurol. 69, 155-167. doi: 10.1097/NEN.0b013e3181cb5af4
7. Arispe, N., and Doh, M. (2002). Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AbetaP (1-40) and (1-42) peptides. FASEB J. 16, 1526-1536. doi: 10.1096/fj.02-0829com
8. Azizi, G., and Mirshafiey, A. (2012). The potential role of proinflammatory and antiinflammatory cytokines in Alzheimer disease pathogenesis. Immunopharmacol. Immunotoxicol. 34, 881-895. doi: 10.3109/08923973.2012.705292
9. Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., et al. (1999). Apolipoprotein E is essential for amyloid deposition in the APP (V717F) transgenic mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U S A 96, 15233-15238. doi: 10.1073/pnas.96.26.15233
10. Beel, A. J., Sakakura, M., Barrett, P. J., and Sanders, C. R. (2010). Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? Biochim Biophys. Acta 1801, 975-982. doi: 10.1016/j.bbalip.2010.03.008
11. Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., et al. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516. doi: 10.1038/nature11087
12. Berthier, A., Lemaire-Ewing, S., Prunet, C., Monier, S., Athias, A., Bessède, G., et al. (2004). Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death Differ. 11, 897-905. doi: 10.1038/sj.cdd.4401434
13. Bhattacharyya, R., and Kovacs, D. M. (2010). ACAT inhibition and amyloid beta reduction. Biochim. Biophys. Acta 1801, 960-965. doi: 10.1016/j.bbalip.2010.04.003
14. Björkhem, I. (2006). Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J. Intern. Med. 260, 493-508. doi: 10.1111/j.1365-2796.2006.01725.x
15. Björkhem, I., and Meaney, S. (2004). Brain cholesterol: long secret life behind a barrier. Arterioscler. Thromb. Vasc. Biol. 24, 806-815. doi: 10.1161/01.atv.0000120374.59826.1b
16. Björkhem, I., Cedazo-Minguez, A., Leoni, V., and Meaney, S. (2009). Oxysterols and neurodegenerative diseases. Mol. Aspects Med. 30, 171-179. doi: 10.1016/j.mam.2009.02.001
17. Block, M. L., Zecca, L., and Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. doi: 10.1038/nrn2038
18. Bogdanovic, N., Bretillon, L., Lund, E. G., Diczfalusy, U., Lannfelt, L., Winblad, B., et al. (2001). On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci. Lett. 314, 45-48. doi: 10.1016/s0304-3940(01)02277-7
19. Bonda, D. J., Wang, X., Perry, G., Nunomura, A., Tabaton, M., Zhu, X., et al. (2010). Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59, 290-294. doi: 10.1016/j.neuropharm.2010.04.005
20. Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G. Q., Xu, Q., et al. (2004). Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527-2534. doi: 10.1523/jneurosci.4315-03.2004
21. Bretillon, L., Sidén, A., Wahlund, L. O., Lütjohann, D., Minthon, L., Crisby, M., et al. (2000). Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci. Lett. 293, 87-90. doi: 10.1016/s0304-3940(00)01466-x
22. Brown, G. C., and Bal-Price, A. (2003). Inflammatory neurodegeneration mediated by nitric oxide, glutamate and mitochondria. Mol. Neurobiol. 27, 325-355. doi: 10.1385/mn:27:3:325
23. Brown, J. 3rd, Theisler, C., Silberman, S., Magnuson, D., Gottardi-Littell, N., Lee, J. M., et al. (2004). Differential expression of cholesterol hydroxylases in Alzheimer's disease. J. Biol. Chem. 279, 34674-34681. doi: 10.1074/jbc.m402324200
24. Braak, H., and Del Tredici, K. (2004). Alzheimer's disease: intraneuronal alterations precede insoluble amyloid-beta formation. Neurobiol. Aging 25, 713-718. doi: 10.1016/j.neurobiolaging.2003.12.015
25. Bu, G. (2009). Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333-344. doi: 10.1038/nrn2620
26. Burns, M. P., Noble, W. J., Olm, V., Gaynor, K., Casey, E., LaFrancois, J., et al. (2003b). Co-localization of cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques. Brain Res. Mol. Brain Res. 110, 119-125. doi: 10.1016/s0169-328x(02)00647-2
27. Burns, M., Gaynor, K., Olm, V., Mercken, M., LaFrancois, J., Wang, L., et al. (2003a). Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo. J. Neurosci. 23, 5645-5649.
28. Butterfield, D. A., and Boyd-Kimball, D. (2005). The critical role of methionine 35 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity. Biochim. Biophys. Acta 1703, 149-156. doi: 10.1016/j.bbapap.2004.10.014
29. Butterfield, D. A., and Kanski, J. (2001). Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech. Ageing Dev. 122, 945-962. doi: 10.1016/s0047-6374(01)00249-4
30. Butterfield, D. A., Drake, J., Pocernich, C., and Castegna, A. (2001). Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol. Med. 7, 548-554. doi: 10.1016/s1471-4914(01)02173-6
31. Butterfield, D. A., Swomley, A. M., and Sultana, R. (2013). Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid. Redox Signal. 19, 823-835. doi: 10.1089/ars.2012.5027
32. Cam, J. A., and Bu, G. (2006). Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family. Mol. Neurodegener. 18, 1-8. doi: 10.1186/1750-1326-1-8
33. Canepa, E., Borghi, R., Viña, J., Traverso, N., Gambini, J., Domenicotti, C., et al. (2011). Cholesterol and amyloid-A: evidence for a cross-talk between astrocytes and neuronal cells. J. Alzheimers Dis. 25, 645-653. doi: 10.3233/JAD-2011-110053
34. Cao, G., Bales, K. R., DeMattos, R. B., and Paul, S. M. (2007). Liver X receptor-mediated gene regulation and cholesterol homeostasis in brain: relevance to Alzheimer's disease therapeutics. Curr. Alzheimer Res. 4, 179-184. doi: 10.2174/156720507780362173
35. Carter, D. B., Dunn, E., McKinley, D. D., Stratman, N. C., Boyle, T. P., Kuiper, S. L., et al. (2001). Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain. Ann. Neurol. 50, 468-475. doi: 10.1002/ana.1134
36. Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J. W., et al. (2005). Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 19, 2040-2041. doi: 10.1096/fj.05-3735fje
37. Castellani, R. J., Rolston, R. K., and Smith, M. A. (2010). Alzheimer disease. Dis. Mon. 56, 484-546. doi: 10.1016/j.disamonth.2010.06.001
38. Castellani, R., Hirai, K., Aliev, G., Drew, K. L., Nunomura, A., Takeda, A., et al. (2002). Role of mitochondrial dysfunction in Alzheimer's disease. J. Neurosci. Res. 70, 357-360. doi: 10.1002/jnr.10389
39. Chan, S. L., Kim, W. S., Kwok, J. B., Hill, A. F., Cappai, R., Rye, K. A., et al. (2008). ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J. Neurochem. 106, 793-804. doi: 10.1111/j.1471-4159.2008.05433.x
40. Chang, S., ran Ma, T., Miranda, R. D., Balestra, M. E., Mahley, R. W., and Huang, Y. (2005). Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc. Natl. Acad. Sci. U S A 102, 18694-18699. doi: 10.1073/pnas.0508254102
41. Chopra, K., Misra, S., and Kuhad, A. (2011). Current perspectives on pharmacotherapy of Alzheimer's disease. Expert Opin. Pharmacother. 12, 335-350. doi: 10.1517/14656566.2011.520702
42. 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: 10.1186/s13041-014-0085-7
43. Colton, C., and Wilcock, D. M. (2010). Assessing activation states in microglia. CNS Neurol. Disord. Drug Targets 9, 174-191. doi: 10.2174/187152710791012053
44. Combs, C. K., Karlo, J. C., Kao, S. C., and Landreth, G. E. (2001). β-amyloid stimulation of microglia anti monocytes results in TNFa-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179-1188.
45. Cordy, J. M., Hooper, N. M., and Turner, A. J. (2006). The involvement of lipid rafts in Alzheimer's disease. Mol. Membr. Biol. 23, 111-122. doi: 10.1080/09687860500496417
46. Cottrell, D. A., Blakely, E. L., Johnson, M. A., Ince, P. G., and Turnbull, D. M. (2001). Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD. Neurology 57, 260-264. doi: 10.1212/wnl.57.2.260
47. Crick, P. J., Beckers, L., Baes, M., Van Veldhoven, P. P., Wang, Y., and Griffiths, W. J. (2015a). The oxysterol and cholestenoic acid profile of mouse cerebrospinal fluid. Steroids doi: 10.1016/j.steroids.2015.02.021 [Epub ahead of print]
48. Crick, P. J., William Bentley, T., Abdel-Khalik, J., Matthews, I., Clayton, P. T., Morris, A. A., et al. (2015b). Quantitative charge-tags for sterol and oxysterol analysis. Clin. Chem. 61, 400-411. doi: 10.1373/clinchem.2014.231332
49. Crouch, P. J., Blake, R., Duce, J. A., Ciccotosto, G. D., Li, Q. X., Barnham, K. J., et al. (2005). Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42. J. Neurosci. 25, 672-679. doi: 10.1523/jneurosci.4276-04.2005
50. Curtain, C. C., Ali, F. E., Smith, D. G., Bush, A. I., Masters, C. L., and Barnham, K. J. (2003). Metal ions, pH and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. J. Biol. Chem. 278, 2977-2982. doi: 10.1074/jbc.m205455200
51. D'Andrea, M. R., Cole, G. M., and Ard, M. D. (2004). The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol. Aging 25, 675-683. doi: 10.1016/j.neurobiolaging.2003.12.026
52. Dasari, B., Prasanthi, J. R., Marwarha, G., Singh, B. B., and Ghribi, O. (2010). The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells. BMC Ophthalmol. 10:22. doi: 10.1186/1471-2415-10-22
53. Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., et al. (2008). ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J. Clin. Invest. 118, 4002-4013. doi: 10.1172/JCI36663
54. DeGiorgio, L. A., Shimizu, Y., Chun, H. S., Kim, Y. S., Sugama, S., Son, J. H., et al. (2002). Amyloid precursor protein gene disruption attenuates degeneration of substantia nigra compacta neurons following axotomy. Brain Res. 938, 38-44. doi: 10.1016/s0006-8993(02)02483-6
55. Dias, I. H., Polidori, M. C., and Griffiths, H. R. (2014). Hypercholesterolaemia-induced oxidative stress at the blood-brain barrier. Biochem. Soc. Trans. 42, 1001-1005. doi: 10.1042/BST20140164
56. Diczfalusy, U. (2013). On the formation and possible biological role of 25-hydroxycholesterol. Biochimie 95, 455-460. doi: 10.1016/j.biochi.2012.06.016
57. Dietschy, J. M. (2009). Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol. Chem. 390, 287-293. doi: 10.1515/BC.2009.035
58. Ding, Q., Dimayuga, E., and Keller, J. N. (2007). Oxidative damage, protein synthesis and protein degradation in Alzheimer's disease. Curr. Alzheimer Res. 4, 73-79. doi: 10.2174/156720507779939788
59. Drouin-Ouellet, J., and Cicchetti, F. (2012). Inflammation and neurodegeneration: the story 'retolled'. Trends Pharmacol. Sci. 33, 542-551. doi: 10.1016/j.tips.2012.07.002
60. Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M., and Yan, S. S. (2010). Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc. Natl. Acad. Sci. U S A 107, 18670-18675. doi: 10.1073/pnas.1006586107
61. Ehehalt, R., Keller, P., Haass, C., Thiele, C., and Simons, K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J. Cell. Biol. 160, 113-123. doi: 10.1083/jcb.200207113
62. Evans, R. M., Hui, S., Perkins, A., Lahiri, D. K., Poirier, J., and Farlow, M. R. (2004). Cholesterol and APOE genotype interact to influence Alzheimer disease progression. Neurology 62, 1869-1871. doi: 10.1212/01.wnl.0000125323.15458.3f
63. Famer, D., Meaney, S., Mousavi, M., Nordberg, A., Björkhem, I., and Crisby, M. (2007). Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway. Biochem. Biophys. Res. Commun. 359, 46-50. doi: 10.1016/j.bbrc.2007.05.033
64. Fan, Q. W., Yu, W., Senda, T., Yanagisawa, K., and Michikawa, M. (2001). Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J. Neurochem. 76, 391-400. doi: 10.1046/j.1471-4159.2001.00063.x
65. Fantini, J., and Yahi, N. (2010). Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Expert Rev. Mol. Med. 12:e27. doi: 10.1017/s1462399410001602
66. Fassbender, K., Masters, C., and Beyreuther, K. (2000). Alzheimer's disease: an inflammatory disease? Neurobiol. Aging 21, 433-436. doi: 10.1016/S0197-4580(00)00147-0
67. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lütjohann, D., Keller, P., 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: 10.1073/pnas.081620098
68. Fernandez-Fernandez, S., Almeida, A., and Bolaños, J. P. (2012). Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3-11. doi: 10.1042/bj20111943
69. Ferrera, P., Mercado-Gómez, O., Silva-Aguilar, M., Valverde, M., and Arias, C. (2008). Cholesterol potentiates beta-amyloid-induced toxicity in human neuroblastoma cells: involvement of oxidative stress. Neurochem. Res. 33, 1509-1517. doi: 10.1007/s11064-008-9623-y
70. Ferretti, M. T., and Cuello, A. C. (2011). Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment? Curr. Alzheimer Res. 8, 164-174. doi: 10.2174/1567211213451702050
71. Figueiredo-Pereira, M. E., Rockwell, P., Schmidt-Glenewinkel, T., and Serrano, P. (2015). Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Front. Mol. Neurosci. 7:104. doi: 10.3389/fnmol.2014.00104
72. Findeis, M. A. (2007). The role of amyloid β peptide 42 in Alzheimer's disease. Pharmacol. Ther. 116, 266-286. doi: 10.1016/j.pharmthera.2007.06.006
73. Fitz, N. F., Cronican, A., Pham, T., Fogg, A., Fauq, A. H., Chapman, R., et al. (2010). LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice. J. Neurosci. 30, 6862-6872. doi: 10.1523/JNEUROSCI.1051-10.2010
74. Gamba, P., Guglielmotto, M., Testa, G., Monteleone, D., Zerbinati, C., Gargiulo, S., et al. (2014). Up-regulation of β-amyloidogenesis in neuron-like human cells by both 24- and 27-hydroxycholesterol: protective effect of N-acetyl-cysteine. Aging Cell. 13, 561-572. doi: 10.1111/acel.12206
75. Gamba, P., Leonarduzzi, G., Tamagno, E., Guglielmotto, M., Testa, G., Sottero, B., et al. (2011). Interaction between 24-hydroxycholesterol, oxidative stress and amyloid-β in amplifying neuronal damage in Alzheimer's disease: three partners in crime. Aging Cell 10, 403-417. doi: 10.1111/j.1474-9726.2011.00681.x
76. Gamba, P., Testa, G., Sottero, B., Gargiulo, S., Poli, G., and Leonarduzzi, G. (2012). The link between altered cholesterol metabolism and Alzheimer's disease. Ann. N Y Acad. Sci. 1259, 54-64. doi: 10.1111/j.1749-6632.2012.06513.x
77. Gate, D., Rezai-Zadeh, K., Jodry, D., Rentsendorj, A., and Town, T. (2010). Macrophages in Alzheimer's disease: the blood-borne identity. J. Neural Transm. 117, 961-970. doi: 10.1007/s00702-010-0422-7
78. Gatz, M., Reynolds, C. A., Fratiglioni, L., Johansson, B., Mortimer, J. A., Berg, S., et al. (2006). Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168-174. doi: 10.1001/archpsyc.63.2.168
79. Ghribi, O., Larsen, B., Schrag, M., and Herman, M. M. (2006). High cholesterol content in neurons increases BACE, A-amyloid and phosphorylated tau levels in rabbit hippocampus. Exp. Neurol. 200, 460-467. doi: 10.1016/j.expneurol.2006.03.019
80. Giraldo, E., Lloret, A., Fuchsberger, T., and Viña, J. (2014). Aβ and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E. Redox Biol. 2, 873-877. doi: 10.1016/j.redox.2014.03.002
81. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., and Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934. doi: 10.1016/j.cell.2010.02.016
82. Gong, J. S., Sawamura, N., Zou, K., Sakai, J., Yanagisawa, K., and Michikawa, M. (2002). Amyloid beta-protein affects cholesterol metabolism in cultured neurons: implications for pivotal role of cholesterol in the amyloid cascade. J. Neurosci. Res. 70, 438-446. doi: 10.1002/jnr.10347
83. Götz, J., Chen, F., van Dorpe, J., and Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293, 1491-1495. doi: 10.1126/science.1062097
84. Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., et al. (2009). Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361-1363. doi: 10.1038/nn.2432
85. Grimm, M. O., Grimm, H. S., Tomic, I., Beyreuther, K., Hartmann, T., and Bergmann, C. (2008). Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels. J. Biol. Chem. 283, 11302-11311. doi: 10.1074/JBC.M801520200
86. Harris, B., Pereira, I., and Parkin, E. (2009). Targeting ADAM10 to lipid rafts in neuroblastoma SH-SY5Y cells impairs amyloidogenic processing of the amyloid precursor protein. Brain Res. 1296, 203-215. doi: 10.1016/j.brainres.2009.07.105
87. Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., et al. (2003). Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. U S A 100, 10966-10971. doi: 10.1073/pnas.1434398100
88. Harris, J. R. (2008). Cholesterol binding to amyloid-beta fibrils: a TEM study. Micron 39, 1192-1196. doi: 10.1016/j.micron.2008.05.001
89. Hascalovici, J. R., Vaya, J., Khatib, S., Holcroft, C. A., Zukor, H., Song, W., et al. (2009). Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1. J. Neurochem. 110, 1241-1253. doi: 10.1111/j.1471-4159.2009.06213.x
90. Hawkes, C. A., and McLaurin, J. (2009). Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc. Natl. Acad. Sci. U S A 106, 1261-1266. doi: 10.1073/pnas.0805453106
91. He, X., Jenner, A. M., Ong, W. Y., Farooqui, A. A., and Patel, S. C. (2006). Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury. J. Neuropathol. Exp. Neurol. 65, 652-663. doi: 10.1097/01.jnen.0000225906.82428.69
92. Head, E., Lott, I. T., Cribbs, D. H., Cotman, C. W., and Rohn, T. T. (2002). Beta-amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome. Neurosci. Lett. 330, 99-103. doi: 10.1016/s0304-3940(02)00705-x
93. Heneka, M. T., and O'Banion, M. K. (2007). Inflammatory processes in Alzheimer's disease. J. Neuroimmunol. 184, 69-91. doi: 10.1016/j.jneuroim.2006.11.017
94. Heneka, M. T., O'Banion, M. K., Terwel, D., and Kummer, M. P. (2010). Neuroinflammatory processes in Alzheimer's disease. J Neural Transm. 117, 919-947. doi: 10.1007/s00702-010-0438-z
95. Herz, J., and Beffert, U. (2000). Apolipoprotein E receptors: linking brain development and Alzheimer's disease. Nat. Rev. Neurosci. 1, 51-58. doi: 10.1038/35036221
96. Heverin, M., Bogdanovic, N., Lütjohann, D., Bayer, T., Pikuleva, I., Bretillon, L., et al. (2004). Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J. Lipid Res. 45, 186-193. doi: 10.1194/jlr.m300320-jlr200
97. Heverin, M., Meaney, S., Lütjohann, D., Diczfalusy, U., Wahren, J., and Björkhem, I. (2005). Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain. J. Lipid Res. 46, 1047-1052. doi: 10.1194/jlr.m500024-jlr200
98. Hickman, S. E., Allison, E. K., and El Khoury, J. (2008). Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354-8360. doi: 10.1523/JNEUROSCI.0616-08.2008
99. Holmes, C. (2013). Review: systemic inflammation and Alzheimer's disease. Neuropathol. Appl. Neurobiol. 39, 51-68. doi: 10.1111/j.1365-2990.2012.01307.x
100. Holmes, C., and Butchart, J. (2011). Systemic inflammation and Alzheimer's disease. Biochem. Soc. Trans. 39, 898-901. doi: 10.1042/BST0390898
101. Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., et al. (2000). Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U S A 97, 2892-2897. doi: 10.1073/pnas.050004797
102. Hooijmans, C. R., Rutters, F., Dederen, P. J., Gambarota, G., Veltien, A., van Groen, T., et al. (2007). Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol. Dis. 28, 16-29. doi: 10.1016/j.nbd.2007.06.007
103. Hughes, T. M., Kuller, L. H., Lopez, O. L., Becker, J. T., Evans, R. W., Sutton-Tyrrell, K., et al. (2012). Markers of cholesterol metabolism in the brain show stronger association with cerebrovascular disease than Alzheimer's disease. J. Alzheimers Dis. 30, 53-61. doi: 10.3233/JAD-2012-111460
104. Hughes, T. M., Lopez, O. L., Evans, R. W., Kamboh, M. I., Williamson, J. D., Klunk, W. E., et al. (2014). Markers of cholesterol transport are associated with amyloid deposition in the brain. Neurobiol. Aging 35, 802-807. doi: 10.1016/j.neurobiolaging.2013.09.040
105. Hughes, T. M., Rosano, C., Evans, R. W., and Kuller, L. H. (2013). Brain cholesterol metabolism, oxysterols and dementia. J. Alzheimers Dis. 33, 891-911. doi: 10.3233/JAD-2012-121585
106. Iadecola, C. (2004). Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347-360. doi: 10.1038/nrn1387
107. Iuliano, L. (2011). Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chem. Phys. Lipids 164, 457-458. doi: 10.1016/j.chemphyslip.2011.06.006
108. Iuliano, L., Crick, P. J., Zerbinati, C., Tritapepe, L., Abdel-Khalik, J., Poirot, M., et al. (2015). Cholesterol metabolites exported from human brai. Steroids doi: 10.1016/j.steroids.2015.01.026 [Epub ahead of print]
109. Iuliano, L., Monticolo, R., Straface, G., Spoletini, I., Gianni, W., Caltagirone, C., et al. (2010). Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer's disease. J. Alzheimers Dis. 21, 1383-1392. doi: 10.3233/JAD-2010-100780
110. Jacob, K. D., Noren Hooten, N., Trzeciak, A. R., and Evans, M. K. (2013). Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech. Ageing Dev. 134, 139-157. doi: 10.1016/j.mad.2013.02.008
111. Jang, E. R., and Lee, C. S. (2011). 7-ketocholesterol induces apoptosis in differentiated PC12 cells via reactive oxygen species-dependent activation of NF-?B and Akt pathways. Neurochem. Int. 58, 52-59. doi: 10.1016/j.neuint.2010.10.012
112. Jaya Prasanthi, R. P., Schommer, E., Thomasson, S., Thompson, A., Feist, G., and Ghribi, O. (2008). Regulation of beta-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer's disease. Mech. Ageing Dev. 129, 649-655. doi: 10.1016/j.mad.2008.09.002
113. Jeitner, T. M., Voloshyna, I., and Reiss, A. B. (2011). Oxysterol derivatives of cholesterol in neurodegenerative disorders. Curr. Med. Chem. 18, 1515-1525. doi: 10.2174/092986711795328445
114. Jenner, A. M., Lim, W. L., Ng, M. P., Wenk, M. R., Shui, G., Sharman, M. J., et al. (2010). The effect of APOE genotype on brain levels of oxysterols in young and old human APOE epsilon2, epsilon3 and epsilon4 knock-in mice. Neuroscience 169, 109-115. doi: 10.1016/j.neuroscience.2010.04.026
115. Ji, Z. S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., and Mahley, R. W. (2002). Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells. J. Biol. Chem. 277, 21821-21828. doi: 10.1074/jbc.m112109200
116. Jiang, Q., Lee, C. Y., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., et al. (2008). ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681-693. doi: 10.1016/j.neuron.2008.04.010
117. Jo, W. K., Law, A. C., and Chung, S. K. (2014). The neglected co-star in the dementia drama: the putative roles of astrocytes in the pathogeneses of major neurocognitive disorders. Mol. Psychiatry 19, 159-167. doi: 10.1038/mp.2013.171
118. Joshi, Y. B., and Praticò, D. (2015). The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer's disease phenotype. Front. Cell Neurosci. 8:436. doi: 10.3389/fncel.2014.00436
119. Kakio, A., Nishimoto, S. I., Yanagisawa, K., Kozutsumi, Y., and Matsuzaki, K. (2001). Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 276, 24985-24990. doi: 10.1074/jbc.m100252200
120. Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., and Matsuzaki, K. (2002). Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41, 7385-7390. doi: 10.1021/bi0255874
121. Keene, C. D., Cudaback, E., Li, X., Montine, K. S., and Montine, T. J. (2011). Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr. Opin. Neurobiol. 21, 920-928. doi: 10.1016/j.conb.2011.08.002
122. Khandelwal, P. J., Herman, A. M., and Moussa, C. E. (2011). Inflammation in the early stages of neurodegenerative pathology. J. Neuroimmunol. 238, 1-11. doi: 10.1016/j.jneuroim.2011.07.002
123. Kierdorf, K., Wang, Y., and Neumann, H. (2010).. Immune-mediated CNS damage. Results Probl. Cell Differ. 51, 173-196. doi: 10.1007/400_2008_15
124. Kim, D. H., and Frangos, J. A. (2008). Effects of amyloid beta-peptides on the lysis tension of lipid bilayer vesicles containing oxysterols. Biophys. J. 95, 620-628. doi: 10.1529/biophysj.107.114983
125. Kim, H. A., Miller, A. A., Drummond, G. R., Thrift, A. G., Arumugam, T. V., Phan, T. G., et al. (2012). Vascular cognitive impairment and Alzheimer's disease: role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch. Pharmacol. 385, 953-959. doi: 10.1007/s00210-012-0790-7
126. Kim, J. H., Jittiwat, J., Ong, W. Y., Farooqui, A. A., and Jenner, A. M. (2010). Changes in cholesterol biosynthetic and transport pathways after excitotoxicity. J. Neurochem. 112, 34-41. doi: 10.1111/j.1471-4159.2009.06449.x
127. Kim, J., Basak, J. M., and Holtzman, D. M. (2009a). The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287-303. doi: 10.1016/j.neuron.2009.06.026
128. Kim, W. S., Chan, S. L., Hill, A. F., Guillemin, G. J., and Garner, B. (2009b). Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons. J. Alzheimers Dis. 16, 121-131. doi: 10.3233/JAD-2009-0944
129. Kim, W. S., Hill, A. F., Fitzgerald, M. L., Freeman, M. W., Evin, G., and Garner, B. (2011). Wild type and tangier disease ABCA1 mutants modulate cellular amyloid-A production independent of cholesterol efflux activity. J. Alzheimers Dis. 27, 441-452. doi: 10.3233/JAD-2011-110521
130. Kim, Y. J., and Lee, C. S. (2010). Tyrosine kinase inhibitor AG126 reduces 7-ketocholesterol-induced cell death by suppressing mitochondria-mediated apoptotic process. Neurochem. Res. 35, 603-612. doi: 10.1007/s11064-009-0105-7
131. Kim, Y. J., Han, J. H., Han, E. S., and Lee, C. S. (2006). 7-Ketocholesterol enhances 1-methyl-4-phenylpyridinium-induced mitochondrial dysfunction and cell death in PC12 cells. J. Neural Transm. 113, 1877-1885. doi: 10.1007/s00702-006-0486-6
132. Koldamova, R. P., Lefterov, I. M., Ikonomovic, M. D., Skoko, J., Lefterov, P. I., Isanski, B. A., et al. (2003). 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion. J. Biol. Chem. 278, 13244-13256. doi: 10.1074/jbc.m300044200
133. Koldamova, R., Fitz, N. F., and Lefterov, I. (2010). The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim. Biophys. Acta 1801, 824-830. doi: 10.1016/j.bbalip.2010.02.010
134. Koudinov, A. R., and Koudinova, N. V. (2005). Cholesterol homeostasis failure as a unifying cause of synaptic degeneration. J. Neurol. Sci. 229-230, 233-240. doi: 10.1016/j.jns.2004.11.036
135. Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., et al. (2013). Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8:e60921. doi: 10.1371/journal.pone.0060921
136. Kölsch, H., Heun, R., Kerksiek, A., Bergmann, K. V., Maier, W., and Lütjohann, D. (2004). Altered levels of plasma 24S- and 27-hydroxycholesterol in demented patients. Neurosci. Lett. 368, 303-308. doi: 10.1016/j.neulet.2004.07.031
137. Kölsch, H., Ludwig, M., Lütjohann, D., Prange, W., and Rao, M. L. (2000). 7alpha-Hydroperoxycholesterol causes CNS neuronal cell death. Neurochem. Int. 36, 507-512. doi: 10.1016/s0197-0186(99)00157-6
138. Kölsch, H., Ludwig, M., Lütjohann, D., and Rao, M. L. (2001). Neurotoxicity of 24-hydroxycholesterol, an important cholesterol elimination product of the brain, may be prevented by vitamin E and estradiol-17beta. J. Neural. Transm. 108, 475-488. doi: 10.1007/s007020170068
139. Lane-Donovan, C., Philips, G. T., and Herz, J. (2014). More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration. Neuron 83, 771-787. doi: 10.1016/j.neuron.2014.08.005
140. Latta, C. H., Brothers, H. M., and Wilcock, D. M. (2014). Neuroinflammation in Alzheimer's disease; A source of heterogeneity and target for personalized therapy. Neuroscience doi: 10.1007/978-1-4615-5405-9_3 [Epub ahead of print]
141. Lee, C. Y., Tse, W., Smith, J. D., and Landreth, G. E. (2011). ApoE promotes AA trafficking and degradation by modulating microglial cholesterol levels. J. Biol. Chem. 287, 2032-2044. doi: 10.1074/jbc.M111.295451
142. Leoni, V., and Caccia, C. (2011). Oxysterols as biomarkers in neurodegenerative diseases. Chem.Phys. Lipids 164, 515-524. doi: 10.1016/j.chemphyslip.2011.04.002
143. Leoni, V., Masterman, T., Mousavi, F. S., Wretlind, B., Wahlund, L. O., Diczfalusy, U., et al. (2004). Diagnostic use of cerebral and extracerebral oxysterols. Clin. Chem. Lab. Med. 42, 186-191. doi: 10.1515/cclm.2004.034
144. Leoni, V., Masterman, T., Patel, P., Meaney, S., Diczfalusy, U., and Björkhem, I. (2003). Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers. J. Lipid Res. 44, 793-799. doi: 10.1194/jlr.m200434-jlr200
145. Lewis, J., Dickson, D. W., Lin, W. L., Chisholm, L., Corral, A., Jones, G., et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487-1491. doi: 10.1126/science.1058189
146. Liu, B., and Hong, J. S. (2003). Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 1-7. doi: 10.1124/jpet.102.035048
147. Liu, Q., Zerbinatti, C. V., Zhang, J., Hoe, H. S., Wang, B., Cole, S. L., et al. (2007). Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56, 66-78. doi: 10.1016/j.neuron.2007.08.008
148. Luchsinger, J. A., and Mayeux, R. (2004). Dietary factors and Alzheimer's disease. Lancet. Neurol. 3, 579-587. doi: 10.1016/S1474-4422(04)00878-6
149. Luckhoff, H. K., Brand, T., van Velden, D. P., Kidd, M., Fisher, L. R., van Rensburg, S. J., et al. (2015). Clinical relevance of apolipoprotein e genotyping based on a family history of Alzheimer's disease. Curr. Alzheimer Res. 12, 210-217. doi: 10.2174/1567205012666150302154354
150. Luque-Contreras, D., Carvajal, K., Toral-Rios, D., Franco-Bocanegra, D., and Campos-Peña, V. (2014). Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer's disease? Oxid. Med. Cell. Longev. 2014:497802. doi: 10.1155/2014/497802
151. Lyman, M., Lloyd, D. G., Ji, X., Vizcaychipi, M. P., and Ma, D. (2014). Neuroinflammation: the role and consequences. Neurosci. Res. 79, 1-12. doi: 10.1016/j.neures.2013.10.004
152. Lütjohann, D., Papassotiropoulos, A., Björkhem, I., Locatelli, S., Bagli, M., Oehring, R. D., et al. (2000). Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J. Lipid Res. 41, 195-198.
153. Ma, M. T., Zhang, J., Farooqui, A. A., Chen, P., and Ong, W. Y. (2010). Effects of cholesterol oxidation products on exocytosis. Neurosci. Lett. 476, 36-41. doi: 10.1016/j.neulet.2010.03.078
154. Ma, W. W., Li, C. Q., Yu, H. L., Zhang, D. D., Xi, Y. D., Han, J., et al. (2015). The oxysterol 27-hydroxycholesterol increases oxidative stress and regulate nrf2 signaling pathway in astrocyte cells. Neurochem. Res. 40, 758-766. doi: 10.1007/s11064-015-1524-2
155. Maezawa, I., Maeda, N., Montine, T. J., and Montine, K. S. (2006a). Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. J. Neuroinflammation 7, 3-10. doi: 10.1186/1742-2094-3-10
156. Maezawa, I., Nivison, M., Montine, K. S., Maeda, N., and Montine, T. J. (2006b). Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. FASEB J. 20, 797-799. doi: 10.1096/fj.05-5423fje
157. Maezawa, I., Zaja-Milatovic, S., Milatovic, D., Stephen, C., Sokal, I., Maeda, N., et al. (2006c). Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity. J. Neuroinflammation 25, 3-21. doi: 10.1186/1742-2094-3-21
158. Malaplate-Armand, C., Florent-Béchard, S., Youssef, I., Koziel, V., Sponne, I., Kriem, B., et al. (2006). Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol. Dis. 23, 178-189. doi: 10.1016/j.nbd.2006.02.010
159. Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., and Reddy, P. H. (2006). Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437-1449. doi: 10.1093/hmg/ddl066
160. Mariani, E., Polidori, M. C., Cherubini, A., and Mecocci, P. (2005). Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 827, 65-75. doi: 10.1016/j.jchromb.2005.04.023
161. Martin, I., and Grotewiel, M. S. (2006). Oxidative damage and age-related functional declines. Mech. Ageing Dev. 127, 411-423. doi: 10.1016/j.mad.2006.01.008
162. Martins, I. J., Berger, T., Sharman, M. J., Verdile, G., Fuller, S. J., and Martins, R. N. (2009). Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease. J. Neurochem. 111, 1275-1308. doi: 10.1111/j.1471-4159.2009.06408.x
163. Marwarha, G., Dasari, B., Prasanthi, J. R., Schommer, J., and Ghribi, O. (2010). Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices. J. Alzheimers Dis. 19, 1007-1019. doi: 10.3233/JAD-2010-1298
164. Marwarha, G., and Ghribi, O. (2014). Does the oxysterol 27-hydroxycholesterol underlie Alzheimer's disease-Parkinson's disease overlap? Exp. Gerontol. doi: 10.1016/j.exger.2014.09.013 [Epub ahead of print]
165. Marwarha, G., Raza, S., Prasanthi, J. R., and Ghribi, O. (2013). Gadd153 and NF-?B crosstalk regulates 27-hydroxycholesterol-induced increase in BACE1 and β-amyloid production in human neuroblastoma SH-SY5Y cells. PLoS One 8:e70773. doi: 10.1371/journal.pone.0070773
166. Marzolo, M. P., and Bu, G. (2009). Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease. Semin. Cell Dev. Biol. 20, 191-200. doi: 10.1016/j.semcdb.2008.10.005
167. Mateos, L., Ismail, M. A., Gil-Bea, F. J., Leoni, V., Winblad, B., Björkhem, I., et al. (2011). Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease. J. Alzheimers Dis. 24, 669-679. doi: 10.3233/JAD-2011-101512
168. Mattson, M. P. (2004). Pathways towards and away from Alzheimer's disease. Nature 430, 631-639. doi: 10.1038/nature02621
169. Mayeux, R. (2003). Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 26, 81-104. doi: 10.1146/annurev.neuro.26.043002.094919
170. Mazzetti, A. P., Fiorile, M. C., Primavera, A., and Lo Bello, M. (2015). Glutathione transferases and neurodegenerative diseases. Neurochem. Int. 82, 10-18. doi: 10.1016/j.neuint.2015.01.008
171. McGeer, E. G., and McGeer, P. L. (2010). Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy. J. Alzheimers Dis. 19, 355-361. doi: 10.3233/JAD-2010-1219
172. McLellan, M. E., Kajdasz, S. T., Hyman, B. T., and Bacskai, B. J. (2003). In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy. J. Neurosci. 23, 2212-2217.
173. Meaney, S., Heverin, M., Panzenboeck, U., Ekström, L., Axelsson, M., Andersson, U., et al. (2007). Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid. J. Lipid Res. 48, 944-951. doi: 10.1194/jlr.m600529-jlr200
174. Melov, S., Adlard, P. A., Morten, K., Johnson, F., Golden, T. R., Hinerfeld, D., et al. (2007). Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2:e536. doi: 10.1371/journal.pone.0000536
175. Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., and Heuschling, P. (2009). Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J. Neuroimmunol. 210, 3-12. doi: 10.1016/j.jneuroim.2009.02.003
176. Michikawa, M., Gong, J. S., Fan, Q. W., Sawamura, N., and Yanagisawa, K. (2001). A novel action of alzheimer's amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J. Neurosci. 21, 7226-7235.
177. Misonou, H., Morishima-Kawashima, M., and Ihara, Y. (2000). Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 39, 6951-6959. doi: 10.1021/bi000169p
178. Mitomo, H., Chen, W. H., and Regen, S. L. (2009). Oxysterol-induced rearrangement of the liquid-ordered phase: a possible link to Alzheimer's disease? J. Am. Chem. Soc. 131, 12354-12357. doi: 10.1021/ja904308y
179. Morales, I., Guzmán-Martínez, L., Cerda-Troncoso, C., Farías, G. A., and Maccioni, R. B. (2014). Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front. Cell Neurosci. 8:112. doi: 10.3389/fncel.2014.00112
180. Morales, I., Jiménez, J. M., Mancilla, M., and Maccioni, R. B. (2013). Tau oligomers and fibrils induce activation of microglial cells. J. Alzheimers Dis. 37, 849-856. doi: 10.3233/JAD-131843
181. Mori, T., Paris, D., Town, T., Rojiani, A. M., Sparks, D. L., Delledonne, A., et al. (2001). Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J. Neuropathol. Exp. Neurol. 60, 778-785.
182. Mrak, R. E. (2012). Microglia in Alzheimer brain: a neuropathological perspective. Int. J. Alzheimers Dis. 2012:165021. doi: 10.1155/2012/165021
183. Mrak, R. E., and Griffin, W. S. (2005). Glia and their cytokines in progression of neurodegeneration. Neurobiol. Aging 26, 349-354. doi: 10.1016/j.neurobiolaging.2004.05.010
184. Mungarro-Menchaca, X., Ferrera, P., Morán, J., and Arias, C. (2002). beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine. J. Neurosci. Res. 68, 89-96. doi: 10.1002/jnr.10193
185. Murphy, P. G., Borthwick, L. S., Johnston, R. S., Kuchel, G., and Richardson, P. M. (1999). Nature of the retrograde signal from injured nerves that induces interleukin-6 mRNA in neurons. J. Neurosci. 19, 3791-3800.
186. Naylor, R., Hill, A. F., and Barnham, K. J. (2008). Neurotoxicity in Alzheimer's disease: is covalently crosslinked A beta responsible? Eur. Biophys. J. 37, 265-268. doi: 10.1007/s00249-007-0243-2
187. Nelson, T. J., and Alkon, D. L. (2005). Oxidation of cholesterol by amyloid precursor protein and beta-amyloid peptide. J. Biol. Chem. 280, 7377-7387. doi: 10.1074/jbc.m409071200
188. 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: 10.1111/j.1471-4159.2009.05917.x
189. Noguchi, N., Saito, Y., and Urano, Y. (2014). Diverse functions of 24(S)-hydroxycholesterol in the brain. Biochem. Biophys. Res. Commun. 446, 692-696. doi: 10.1016/j.bbrc.2014.02.010
190. Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., et al. (2001). Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759-767.
191. Nury, T., Samadi, M., Zarrouk, A., Riedinger, J. M., and Lizard, G. (2013). Improved synthesis and in vitro evaluation of the cytotoxic profile of oxysterols oxidized at C4 (4α- and 4β-hydroxycholesterol) and C7 (7-ketocholesterol, 7α- and 7β-hydroxycholesterol) on cells of the central nervous system. Eur. J. Med. Chem. 70, 558-567. doi: 10.1016/j.ejmech.2013.09.028
192. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409-421. doi: 10.1016/s0896-6273(03)00434-3
193. Okabe, A., Urano, Y., Itoh, S., Suda, N., Kotani, R., Nishimura, Y., et al. (2013). Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death. Redox Biol. 2, 28-35. doi: 10.1016/j.redox.2013.11.007
194. Panza, F., D'Introno, A., Colacicco, A. M., Capurso, C., Pichichero, G., Capurso, S. A., et al. (2006). Lipid metabolism in cognitive decline and dementia. Brain Res. Rev. 51, 275-292. doi: 10.1016/j.brainresrev.2005.11.007
195. Papassotiropoulos, A., Lambert, J. C., Wavrant-De Vrièze, F., Wollmer, M. A., von der Kammer, H., Streffer, J. R., et al. (2005). Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease. Neurodegener. Dis. 2, 233-241. doi: 10.1159/000090362
196. Papassotiropoulos, A., Lütjohann, D., Bagli, M., Locatelli, S., Jessen, F., Buschfort, R., et al. (2002). 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J. Psychiatr. Res. 36, 27-32. doi: 10.1016/s0022-3956(01)00050-4
197. Park, L., Zhou, P., Pitstick, R., Capone, C., Anrather, J., Norris, E. H., et al. (2008). Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl. Acad. Sci. U S A 105, 1347-1352. doi: 10.1073/pnas.0711568105
198. Perry, V. H., Nicoll, J. A., and Holmes, C. (2010). Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193-201. doi: 10.1038/nrneurol.2010.17
199. Pfrieger, F. W. (2003). Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 25, 72-78. doi: 10.1002/bies.10195
200. Phan, H. T., Hata, T., Morita, M., Yoda, T., Hamada, T., Vestergaard, M. C., et al. (2013). The effect of oxysterols on the interaction of Alzheimer's amyloid beta with model membranes. Biochim. Biophys. Acta 1828, 2487-2495. doi: 10.1016/j.bbamem.2013.06.021
201. Popescu, B. O., Toescu, E. C., Popescu, L. M., Bajenaru, O., Muresanu, D. F., Schultzberg, M., et al. (2009). Blood-brain barrier alterations in ageing and dementia. J. Neurol. Sci. 283, 99-106. doi: 10.1016/j.jns.2009.02.321
202. Prasanthi, J. R., Huls, A., Thomasson, S., Thompson, A., Schommer, E., and Ghribi, O. (2009). Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol. Neurodegener. 4:1. doi: 10.1186/1750-1326-4-1
203. Praticò, D., Uryu, K., Leight, S., Trojanoswki, J. Q., and Lee, V. M. (2001). Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183-4187.
204. Puglielli, L., Friedlich, A. L., Setchell, K. D., Nagano, S., Opazo, C., Cherny, R. A., et al. (2005). Alzheimer disease beta-amyloid activity mimics cholesterol oxidase. J. Clin. Invest. 115, 2556-2563. doi: 10.1172/JCI23610
205. Puglielli, L., Konopka, G., Pack-Chung, E., Ingano, L. A., Berezovska, O., Hyman, B. T., et al. (2001). Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat. Cell Biol. 3, 905-912. doi: 10.1038/ncb1001-905
206. Puglielli, L., Tanzi, R. E., and Kovacs, D. M. (2003). Alzheimer's disease: the cholesterol connection. Nat. Neurosci. 6, 345-351. doi: 10.1038/nn0403-345
207. Qiu, L., Buie, C., Reay, A., Vaughn, M. W., and Cheng, K. H. (2011). Molecular dynamics simulations reveal the protective role of cholesterol in β-amyloid protein-induced membrane disruptions in neuronal membrane mimics. J. Phys. Chem. B. 115, 9795-9812. doi: 10.1021/jp2012842
208. Querfurth, H. W., and LaFerla, F. M. (2010). Alzheimer's disease. N. Engl. J. Med. 362, 329-344. doi: 10.1056/NEJMra0909142
209. Quintanilla, R. A., Orellana, J. A., and von Bernhardi, R. (2012). Understanding risk factors for Alzheimer's disease: interplay of neuroinflammation, connexin-based communication and oxidative stress. Arch. Med. Res. 43, 632-644. doi: 10.1016/j.arcmed.2012.10.016
210. Raber, J., Huang, Y., and Ashfordm, J. W. (2004). ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol. Aging 25, 641-650. doi: 10.1016/j.neurobiolaging.2003.12.023
211. Racková, L. (2013). Cholesterol load of microglia: contribution of membrane architecture changes to neurotoxic power? Arch Biochem Biophys. 537, 91-103. doi: 10.1016/j.abb.2013.06.015
212. Ramesh, G., MacLean, A. G., and Philipp, M. T. (2013). Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration and neuropathic pain. Mediators Inflamm. 2013:480739. doi: 10.1155/2013/480739
213. Reddy, P. H. (2011). Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria and synaptic deprivation in Alzheimer's disease. Brain Res. 1415, 136-148. doi: 10.1016/j.brainres.2011.07.052
214. Reddy, P. H., and Beal, M. F. (2005). Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res. Brain Res. Rev. 49, 618-632. doi: 10.1016/j.brainresrev.2005.03.004
215. Reddy, P. H., and Beal, M. F. (2008). Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol. Med. 14, 45-53. doi: 10.1016/j.molmed.2007.12.002
216. Reddy, P. H., McWeeney, S., Park, B. S., Manczak, M., Gutala, R. V., Partovi, D., et al. (2004). Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum. Mol. Genet. 13, 1225-1240. doi: 10.1093/hmg/ddh140
217. Reed, T. T. (2011). Lipid peroxidation and neurodegenerative disease. Free Radic. Biol. Med. 51, 1302-1319. doi: 10.1016/j.freeradbiomed.2011.06.027
218. Refolo, L. M., Malester, B., LaFrancois, J., Bryant-Thomas, T., Wang, R., Tint, G. S., et al. (2000). Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 4, 321-331. doi: 10.1006/nbdi.2000.0304
219. Reid, P. C., Urano, Y., Kodama, T., and Hamakubo, T. (2007). Alzheimer's disease: cholesterol, membrane rafts, isoprenoids and statins. J. Cell Mol. Med. 11, 383-392. doi: 10.1111/j.1582-4934.2007.00054.x
220. Resende, R., Moreira, P. I., Proença, T., Deshpande, A., Busciglio, J., Pereira, C., et al. (2008). Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic. Biol. Med. 44, 2051-2057. doi: 10.1016/j.freeradbiomed.2008.03.012
221. Reynolds, A., Laurie, C., Mosley, R. L., and Gendelman, H. E. (2007). Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol. 82, 297-325. doi: 10.1016/s0074-7742(07)82016-2
222. Rezai-Zadeh, K., Gate, D., Gowing, G., and Town, T. (2011). How to get from here to there: macrophage recruitment in Alzheimer's disease. Curr. Alzheimer Res. 8, 156-163. doi: 10.2174/1567211213451662050
223. Rosales-Corral, S., Reiter, R. J., Tan, D. X., Ortiz, G. G., and Lopez-Armas, G. (2010). Functional aspects of redox control during neuroinflammation. Antioxid Redox Signal. 13, 193-247. doi: 10.1089/ars.2009.2629
224. Roßner, S., Lange-Dohna, C., Zeitschel, U., and Perez-Polo, J. R. (2005). Alzheimer's disease β-secretase BACE1 is not a neuron-specific enzyme. J. Neurochem. 92, 226-234. doi: 10.1111/j.1471-4159.2004.02857.x
225. Royer, M. C., Lemaire-Ewing, S., Desrumaux, C., Monier, S., Pais de Barros, J. P., Athias, A., et al. (2009). 7-ketocholesterol incorporation into sphingolipid/cholesterol-enriched (lipid raft) domains is impaired by vitamin E: a specific role for alpha-tocopherol with consequences on cell death. J. Biol. Chem. 284, 15826-15834. doi: 10.1074/jbc.m808641200
226. Rubio-Perez, J. M., and Morillas-Ruiz, J. M. (2012). A review: inflammatory process in Alzheimer's disease, role of cytokines. ScientificWorldJournal. 2012:756357. doi: 10.1100/2012/756357
227. Sagare, A., Deane, R., Bell, R. D., Johnson, B., Hamm, K., Pendu, R., et al. (2007). Clearance of amyloid-beta by circulating lipoprotein receptors. Nat. Med. 13, 1029-1031. doi: 10.1038/nm1635
228. Saint-Pol, J., Candela, P., Boucau, M. C., Fenart, L., and Gosselet, F. (2013). Oxysterols decrease apical-to-basolateral transport of Aβ peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells. Brain Res. 1517, 1-15. doi: 10.1016/j.brainres.2013.04.008
229. Saint-Pol, J., Vandenhaute, E., Boucau, M. C., Candela, P., Dehouck, L., Cecchelli, R., et al. (2012). Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-β peptide accumulation. J. Alzheimers Dis. 30, 489-503. doi: 10.3233/JAD-2012-112090
230. Schipper, H. M. (2011). Apolipoprotein E: implications for AD neurobiology, epidemiology and risk assessment. Neurobiol. Aging 32, 778-790. doi: 10.1016/j.neurobiolaging.2009.04.021
231. Schönknecht, P., Lütjohann, D., Pantel, J., Bardenheuer, H., Hartmann, T., von Bergmann, K., et al. (2002). Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer's disease compared to healthy controls. Neurosci. Lett. 324, 83-85. doi: 10.1016/s0304-3940(02)00164-7
232. Serrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., et al. (2013). Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J. Neuropathol Exp Neurol. 72, 462-471. doi: 10.1097/NEN.0b013e3182933788
233. Shafaati, M., Marutle, A., Pettersson, H., Lövgren-Sandblom, A., Olin, M., Pikuleva, I., et al. (2011). Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation. J. Lipid Res. 52, 1004-1010. doi: 10.1194/jlr.m014548
234. Sharma, S., Prasanthi, R. P. J., Schommer, E., Feist, G., and Ghribi, O. (2008). Hypercholesterolemia-induced Abeta accumulation in rabbit brain is associated with alteration in IGF-1 signaling. Neurobiol. Dis. 32, 426-432. doi: 10.1016/j.nbd.2008.08.002
235. Shea, T. B., Rogers, E., Ashline, D., Ortiz, D., and Sheu, M. S. (2002). Apolipoprotein E deficiency promotes increased oxidative stress and compensatory increases in antioxidants in brain tissue. Free Radic. Biol. Med. 33, 1115-1120. doi: 10.1016/s0891-5849(02)01001-8
236. Sheng, J. G., Mrak, R. E., Bales, K. R., Cordell, B., Paul, S. M., and Jones, R. A. (2000). Overexpression of the neuritotrophic cytokine S100beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice. J. Neurochem. 74, 295-301. doi: 10.1046/j.1471-4159.2000.0740295.x
237. Shih, A. Y., Johnson, D. A., Wong, G., Kraft, A. D., Jiang, L., Erb, H., et al. (2003). Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23, 3394-3406.
238. Shobab, L. A., Hsiung, G. Y., and Feldman, H. H. (2005). Cholesterol in Alzheimer's disease. Lancet Neurol. 4, 841-852. doi: 10.1016/S1474-4422(05)70248-9
239. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P., and Rivest, S. (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489-502. doi: 10.1016/j.neuron.2006.01.022
240. Smith, M. A., Rottkamp, C. A., Nunomura, A., Raina, A. K., and Perry, G. (2000). Oxidative stress in Alzheimer's disease. Biochim. Biophys. Acta 1502, 139-144. doi: 10.1016/S0925-4439(00)00040-5
241. Smith, M. A., Zhu, X., Tabaton, M., Liu, G., McKeel, D. W. Jr., Cohen, M. L., et al. (2010). Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J. Alzheimers Dis. 19, 363-372. doi: 10.3233/JAD-2010-1239
242. Sochocka, M., Koutsouraki, E. S., Gasiorowski, K., and Leszek, J. (2013). Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: a new approach to therapy. CNS Neurol. Disord. Drug Targets 12, 870-881. doi: 10.2174/18715273113129990072
243. Sodhi, R. K., and Singh, N. (2013). Liver X receptors: emerging therapeutic targets for Alzheimer's disease. Pharmacol. Res. 72, 45-51. doi: 10.1016/j.phrs.2013.03.008
244. Sottero, B., Gamba, P., Gargiulo, S., Leonarduzzi, G., and Poli, G. (2009). Cholesterol oxidation products and disease: an emerging topic of interest in medicinal chemistry. Curr. Med. Chem. 16, 685-705. doi: 10.2174/092986709787458353
245. Sparks, D. L., Kuo, Y. M., Roher, A., Martin, T., and Lukas, R. J. (2000). Alterations of Alzheimer's disease in the cholesterol-fed rabbit, including vascular inflammation. Preliminary observations. Ann. N Y Acad. Sci. 903, 335-344. doi: 10.1111/j.1749-6632.2000.tb06384.x
246. Steffensen, K. R., Jakobsson, T., and Gustafsson, J. Å. (2013). Targeting liver X receptors in inflammation. Expert Opin. Ther. Targets 17, 977-990. doi: 10.1517/14728222.2013.806490
247. Streit, W. J., Xue, Q. S., Braak, H., and del Tredici, K. (2014). Presence of severe neuroinflammation does not intensify neurofibrillary degeneration in human brain. Glia 62, 96-105. doi: 10.1002/glia.22589
248. Stuart, L. M., Bell, S. A., Stewart, C. R., Silver, J. M., Richard, J., Goss, J. L., et al. (2007). CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex. J. Biol. Chem. 282, 27392-27401. doi: 10.1074/jbc.m702887200
249. Su, B., Wang, X., Lee, H. G., Tabaton, M., Perry, G., Smith, M. A., et al. (2010). Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci. Lett. 468, 267-271. doi: 10.1016/j.neulet.2009.11.010
250. Suzuki, S., Tanaka, K., Nagata, E., Ito, D., Dembo, T., and Fukuuchi, Y. (1999). Cerebral neurons express interleukin-6 after transient forebrain ischemia in gerbils. Neurosci. Lett. 262, 117-120. doi: 10.1016/s0304-3940(99)00051-8
251. Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein-Cline, M., Kanabar, P., et al. (2015). APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data and future perspective. J. Neurochem. 133, 465-488. doi: 10.1111/jnc.13072
252. Takeda, S., Sato, N., and Morishita, R. (2014). Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy. Front. Aging Neurosci. 6:171. doi: 10.3389/fnagi.2014.00171
253. Tamagno, E., Bardini, P., Guglielmotto, M., Danni, O., and Tabaton, M. (2006). The various aggregation states of beta-amyloid 1-42 mediate different effects on oxidative stress, neurodegeneration and BACE-1 expression. Free Radic Biol. Med. 41, 202-212. doi: 10.1016/j.freeradbiomed.2006.01.021
254. Tanzi, R. E., and Bertram, L. (2005). Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545-555. doi: 10.1016/j.cell.2005.02.008
255. Tchelingerian, J. L., Vignais, L., and Jacque, C. (1994). TNF alpha gene expression is induced in neurones after a hippocampal lesion. Neuroreport 5, 585-588. doi: 10.1097/00001756-199401000-00013
256. Terwel, D., Steffensen, K. R., Verghese, P. B., Kummer, M. P., Gustafsson, J. Å., Holtzman, D. M., et al. (2011). Critical role of astroglial apolipoprotein E and liver X receptor-a expression for microglial Aβ phagocytosis. J. Neurosci. 31, 7049-7059. doi: 10.1523/JNEUROSCI.6546-10.2011
257. Testa, G., Gamba, P., Badilli, U., Gargiulo, S., Maina, M., Guina, T., et al. (2014). Loading into nanoparticles improves quercetin's efficacy in preventing neuroinflammation induced by oxysterols. PLoS One 9:e96795. doi: 10.1371/journal.pone.0096795
258. Testa, G., Gamba, P., Di Scipio, F., Sprio, A. E., Salamone, P., Gargiulo, S., et al. (2012). Potentiation of amyloid-β peptide neurotoxicity in human dental neuron-like cells by the membrane lipid peroxidation product 4-hydroxynonenal. Free Radic. Biol. Med. 53, 1708-1717. doi: 10.1016/j.freeradbiomed.2012.08.581
259. Town, T., Nikolic, V., and Tan, J. (2005). The microglial "activation" continuum: from innate to adaptive responses. J. Neuroinflammation 2:24. doi: 10.1186/1742-2094-2-24
260. Urano, Y., Ochiai, S., and Noguchi, N. (2013). Suppression of amyloid-β production by 24S-hydroxycholesterol via inhibition of intracellular amyloid precursor protein trafficking. FASEB J. 27, 4305-4315. doi: 10.1096/fj.13-231456
261. Usui, K., Hulleman, J. D., Paulsson, J. F., Siegel, S. J., Powers, E. T., and Kelly, J. W. (2009). Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity. Proc. Natl. Acad. Sci. U S A 106, 18563-18568. doi: 10.1073/pnas.0804758106
262. Vance, J. E., Hayashi, H., and Karten, B. (2005). Cholesterol homeostasis in neurons and glial cells. Semin. Cell Dev. Biol. 16, 193-212. doi: 10.1016/j.semcdb.2005.01.005
263. Vaya, J., and Schipper, H. M. (2007). Oxysterols, cholesterol homeostasis and Alzheimer disease. J. Neurochem. 102, 1727-1737. doi: 10.1111/j.1471-4159.2007.04689.x
264. Verdier, Y., Zarándi, M., and Penke, B. (2004). Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. J. Pept. Sci. 10, 229-248. doi: 10.1002/psc.573
265. Vetrivel, K. S., and Thinakaran, G. (2010). Membrane rafts in Alzheimer's disease beta-amyloid production. Biochim. Biophys. Acta. 1801, 860-867. doi: 10.1016/j.bbalip.2010.03.007
266. Voloshyna, I., and Reiss, A. B. (2011). The ABC transporters in lipid flux and atherosclerosis. Prog. Lipid Res. 50, 213-224. doi: 10.1016/j.plipres.2011.02.001
267. von Bernhardi, R., Tichauer, J. E., and Eugenín, J. (2010). Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J. Neurochem. 112, 1099-1114. doi: 10.1111/j.1471-4159.2009.06537.x
268. Vukic, V., Callaghan, D., Walker, D., Lue, L. F., Liu, Q. Y., Couraud, P. O., et al. (2009). Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway. Neurobiol. Dis. 34, 95-106. doi: 10.1016/j.nbd.2008.12.007
269. Wahrle, S., Das, P., Nyborg, A. C., McLendon, C., Shoji, M., Kawarabayashi, T., et al. (2002). Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9, 11-23. doi: 10.1006/nbdi.2001.0470
270. Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., et al. (2008). Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J. Clin. Invest. 118, 671-682. doi: 10.1172/jci33622
271. Wahrle, S. E., Jiang, H., Parsadanian, M., Legleiter, J., Han, X., Fryer, J. D., et al. (2004). ABCA1 is required for normal central nervous system APOE levels and for lipidation of astrocyte-secreted APOE. J. Biol. Chem. 279, 40987-40993. doi: 10.1074/jbc.m407963200
272. Walsh, D. M., and Selkoe, D. J. (2007). A beta oligomers - a decade of discovery. J. Neurochem. 101, 1172-1184. doi: 10.1111/j.1471-4159.2006.04426.x
273. Waltl, S., Patankar, J. V., Fauler, G., Nusshold, C., Ullen, A., Eibinger, G., et al. (2013). 25-Hydroxycholesterol regulates cholesterol homeostasis in the murine CATH.a neuronal cell line. Neurosci. Lett. 539, 16-21. doi: 10.1016/j.neulet.2013.01.014
274. Wang, L., Schuster, G. U., Hultenby, K., Zhang, Q., Andersson, S., and Gustafsson, J. A. (2002). Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc. Natl. Acad. Sci. U S A 99, 13878-13883. doi: 10.1073/pnas.172510899
275. Wang, N., Yvan-Charvet, L., Lütjohann, D., Mulder, M., Vanmierlo, T., Kim, T. W., et al. (2008). ATP-binding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain. FASEB J. 22, 1073-1082. doi: 10.1096/fj.07-9944com
276. Wang, Y., Li, M., Tang, J., Song, M., Xu, X., Xiong, J., et al. (2011). Glucocorticoids facilitate astrocytic amyloid-β peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-β-degrading proteases. Endocrinology 152, 2704-2715. doi: 10.1210/en.2011-0145
277. Wegiel, J., Imaki, H., Wang, K. C., Wegiel, J., and Rubenstein, R. (2004). Cells of monocyte/microglial lineage are involved in both microvessel amyloidosis and fibrillar plaque formation in APPsw tg mice. Brain Res. 1022, 19-29. doi: 10.1016/j.brainres.2004.06.058
278. Weitz, T. M., and Town, T. (2012). Microglia in Alzheimer's Disease: It's All About Context. Int. J. Alzheimers Dis. 2012:314185. doi: 10.1155/2012/314185
279. 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. doi: 10.1111/jnc.12637
280. Xiong, H., Callaghan, D., Jones, A., Walker, D. G., Lue, L. F., Beach, T. G., et al. (2008). Cholesterol retention in Alzheimer's brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiol. Dis. 29, 422-437. doi: 10.1016/j.nbd.2007.10.005
281. 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: 10.1523/jneurosci.5476-05.2006
282. Yamanaka, K., Saito, Y., Yamamori, T., Urano, Y., and Noguchi, N. (2011). 24(S)-hydroxycholesterol induces neuronal cell death through necroptosis, a form of programmed necrosis. J. Biol. Chem. 286, 24666-24673. doi: 10.1074/jbc.m111.236273
283. Yan, S. D., Yan, S. F., Chen, X., Fu, J., Chen, M., Kuppusamy, P., et al. (1995). Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat. Med. 1, 693-699. doi: 10.1038/nm0795-693
284. Yanagisawa, K. (2005). Cholesterol and amyloid beta fibrillogenesis. Subcell. Biochem. 38, 179-202. doi: 10.1007/0-387-23226-5_9
285. Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., and Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U S A 106, 14670-14675. doi: 10.1073/pnas.0903563106
286. Yau, J. L., Rasmuson, S., Andrew, R., Graham, M., Noble, J., Olsson, T., et al. (2003). Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease. Neuroscience 121, 307-314. doi: 10.1016/s0306-4522(03)00438-x
287. Ye, S., Huang, Y., Müllendorff, K., Dong, L., Giedt, G., Meng, E. C., et al. (2005). Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc. Natl. Acad. Sci. U S A 102, 18700-18705. doi: 10.1073/pnas.0508693102
288. Yoshimoto, N., Tasaki, M., Shimanouchi, T., Umakoshi, H., and Kuboi, R. (2005). Oxidation of cholesterol catalyzed by amyloid beta-peptide (Abeta)-Cu complex on lipid membrane. J. Biosci. Bioeng. 100, 455-459. doi: 10.1263/jbb.100.455
289. Yu, Y., and Ye, R. D. (2015). Microglial Aβ receptors in Alzheimer's disease. Cell Mol. Neurobiol. 35, 71-83. doi: 10.1007/s10571-014-0101-6
290. Zelcer, N., Khanlou, N., Clare, R., Jiang, Q., Reed-Geaghan, E. G., Landreth, G. E., et al. (2007). Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc. Natl. Acad. Sci. U S A 104, 10601-10606. doi: 10.1073/pnas.0701096104
291. Zhu, X., Lee, H. G., Casadesus, G., Avila, J., Drew, K., Perry, G., et al. (2005). Oxidative imbalance in Alzheimer's disease. Mol. Neurobiol. 31, 205-217. doi: 10.1385/mn:31:1-3:205
292. Zhu, X., Su, B., Wang, X., Smith, M. A., and Perry, G. (2007). Causes of oxidative stress in Alzheimer disease. Cell. Mol. Life Sci. 64, 2202-2210. doi: 10.1007/s00018-007-7218-4