Oxidized cholesterol species as signaling molecules in the brain: diabetes and Alzheimer's disease

Thaddeus K Weigel, Joshua A Kulas, Heather A Ferris, Thaddeus K Weigel, Joshua A Kulas, Heather A Ferris

Abstract

Type 2 diabetes is associated with adverse central nervous system effects, including a doubled risk for Alzheimer's disease (AD) and increased risk of cognitive impairment, but the mechanisms connecting diabetes to cognitive decline and dementia are unknown. One possible link between these diseases may be the associated alterations to cholesterol oxidation and metabolism in the brain. We will survey evidence demonstrating alterations to oxysterols in the brain in AD and diabetes and how these oxysterols could contribute to pathology, as well as identifying research questions that have not yet been addressed to allow for a fuller understanding of the role of oxysterols in AD and diabetes.

Keywords: Alzheimers disease; cholesterol; oxysterols; type 2 diabetes.

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

© 2019 The Author(s).

Figures

Figure 1. Oxysterols in the brain
Figure 1. Oxysterols in the brain
Oxysterols are produced from cholesterol by autoxidation or enzymatic oxidation. Non-enzymatically produced oxysterols include 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC). Other oxysterols are produced predominantly enzymatically, including 24(S)-hydroxycholesterol (24(S)OHC), which is produced exclusively in the brain for cholesterol export to the blood. 7α-Hydroxycholesterol (7αOHC) and 25-hydroxycholesterol (25OHC) are produced both enzymatically and non-enzymatically. 27-Hydroxycholesterol (27OHC) is produced in the periphery and enters the brain through the blood. These oxysterols can contribute to neuroinflammation and decreased cholesterol synthesis, two mechanisms thought to contribute to neurodegeneration.
Figure 2. Microglia activation by oxysterols
Figure 2. Microglia activation by oxysterols
Oxysterols, including 7-ketocholesterol, stimulate microglia by activating toll-like receptors (TLRs). TLR activation drives an intracellular signaling cascade dependent on kinases including Akt, P38, PKC, PI3K, and ERK1/2 [97]. TLR signaling activates PARP-1 enzyme activity and ultimately shifts microglia to a pro-inflammatory activated state. Oxysterol activation of microglia can be prevented by treatment with PPARγ receptor agonists. Oxysterol activated microglia have activated inflammasome markers including increased NLRP3 and caspase 1. iNOS expression is also robustly up-regulated. Activated microglia then secrete a variety of immune signaling molecules including TNFα, CCL2, IL1β,nd nitric oxide.

References

    1. Gudala K., Bansal D., Schifano F. and Bhansali A. (2013) Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J. Diabetes Investig. 4, 640–650 10.1111/jdi.12087
    1. Geijselaers S.L.C., Sep S.J.S., Stehouwer C.D.A. and Biessels G.J. (2015) Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet Diabetes Endocrinol. 3, 75–89 10.1016/S2213-8587(14)70148-2
    1. Roberts R.O., Knopman D.S., Przybelski S.A., Mielke M.M., Kantarci K., Preboske G.M. et al. . (2014) Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology 82, 1132–1141 10.1212/WNL.0000000000000269
    1. Arnold S.E., Arvanitakis Z., Macauley-Rambach S.L., Koenig A.M., Wang H.Y., Ahima R.S. et al. . (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol. 14, 168–181 10.1038/nrneurol.2017.185
    1. Pugazhenthi S., Qin L. and Reddy P.H. (2017) Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 1037–1045 10.1016/j.bbadis.2016.04.017
    1. Exalto L.G., Biessels G.J., Karter A.J., Huang E.S., Katon W.J., Minkoff J.R. et al. . (2013) Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: A cohort study. Lancet Diabetes Endocrinol. 1, 183–190 10.1016/S2213-8587(13)70048-2
    1. Haroon N.N., Austin P.C., Shah B.R., Wu J., Gill S.S. and Booth G.L. (2015) Risk of dementia in seniors with newly diagnosed diabetes: A Population-Based study. Diabetes Care 38, 1868–1875 10.2337/dc15-0491
    1. Whitmer R.A., Karter A.J., Yaffe K., Quesenberry C.P. and Selby J.V. (2009) Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. J. Am. Med. Assoc. 301, 1565–1572 10.1001/jama.2009.460
    1. Bangen K.J., Himali J.J., Beiser A.S., Nation D.A., Libon D.J., Fox C.S. et al. . (2016) Interaction between midlife blood glucose and APOE genotype predicts later Alzheimer’s disease pathology. J. Alzheimer’s Dis. 53, 1553–1562 10.3233/JAD-160163
    1. Macauley S.L., Stanley M., Caesar E.E., Yamada S.A., Raichle M.E., Perez R. et al. . (2015) Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J. Clin. Invest. 125, 2463–2467 10.1172/JCI79742
    1. Chang T.-Y., Yamauchi Y., Hasan M.T. and Chang C. (2017) Cellular cholesterol homeostasis and Alzheimer’s disease. J. Lipid. Res. 58, 2239–2254 10.1194/jlr.R075630
    1. Suzuki R., Lee K., Jing E., Biddinger S.B., McDonald J.G., Montine T.J. et al. . (2010) Diabetes and insulin in regulation of brain cholesterol metabolism. Cell Metab. 12, 567–579 10.1016/j.cmet.2010.11.006
    1. Liu C.-C., Kanekiyo T., Xu H. and Bu G. (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. England: Nat. Publishing Group; Feb 8, 106–118 10.1038/nrneurol.2012.263
    1. 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 10.1074/jbc.M115.664367
    1. Allsopp R.C., Lalo U. and Evans R.J. (2010) Lipid raft association and cholesterol sensitivity of P2X1-4 receptors for ATP. J. Biol. Chem. 285, 32770–32777 10.1074/jbc.M110.148940
    1. Musiek E.S., Xiong D.D. and Holtzman D.M. (2015) Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp. Mol. Med. 47, e148 10.1038/emm.2014.121
    1. Chen J.A., Wang Q., Davis-Turak J., Li Y., Karydas A.M., Hsu S.C. et al. . (2015) A multiancestral genome-wide exome array study of alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy. JAMA Neurol. 72, 414 10.1001/jamaneurol.2014.4040
    1. Lambert J.-C., Ibrahim-Verbaas C.A., Harold D., Naj A.C., Sims R., Bellenguez C. et al. . (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 10.1038/ng.2802
    1. Lambert J.-C., Heath S., Even G., Campion D., Sleegers K., Hiltunen M. et al. . (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 10.1038/ng.439
    1. Steinberg S., Stefansson H., Jonsson T., Johannsdottir H., Ingason A., Helgason H. et al. . (2015) Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat. Genet. 47, 445–447 10.1038/ng.3246
    1. Parsons R.B., Subramaniam D. and Austen B.M. (2007) A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro. J. Neurochem. 102, 1276–1291 10.1111/j.1471-4159.2007.04619.x
    1. van der Kant R., Langness V.F., Herrera C.M., Williams D.A., Fong L.K., Leestemaker Y. et al. . (2019) Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363.e9–375.e9 10.1016/j.stem.2018.12.013
    1. Wolozin B., Kellman W., Ruosseau P., Celesia G.G. and Siegel G. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443 10.1001/archneur.57.10.1439
    1. Jick H., Zornberg G.L., Jick S.S., Seshadri S. and Drachman D.A. (2000) Statins and the risk of dementia. Lancet 356, 1627–1631 10.1016/S0140-6736(00)03155-X
    1. Collins R., Armitage J., Parish S., Sleight P. and Peto R. (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 10.1016/S0140-6736(02)09327-3
    1. Houx P.J., Shepherd J., Blauw G.J., Murphy M.B., Ford I., Bollen E.L. et al. . (2002) Testing cognitive function in elderly populations: The PROSPER study. J. Neurol. Neurosurg. Psychiatry 73, 385–389 10.1136/jnnp.73.4.385
    1. Mcguinness B., Craig D., Bullock R. and Passmore P. (2016) Statins for the prevention of dementia. Cochrane Database System. Rev. 2016, CD003160
    1. Crick P.J., Zerbinati C., Tritapepe L., Abdel-Khalik J., Poirot M., Wang Y. et al. . (2015) Cholesterol metabolites exported from human brain. Steroids 99, 189–193 10.1016/j.steroids.2015.01.026
    1. 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 10.1194/jlr.M500024-JLR200
    1. Ohyama Y., Meaney S., Heverin M., Ekström L., Brafman A., Shafir M. et al. . (2006) Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): marked insensitivity toward different regulatory axes. J. Biol. Chem. 281, 3810–3820 10.1074/jbc.M505179200
    1. Mast N., Anderson K.W., Johnson K.M., Phan T.T.N., Guengerich F.P. and Pikuleva I.A. (2017) In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds. J. Biol. Chem 292, 12934–12946 10.1074/jbc.M117.794909
    1. Shafaati M., Mast N., Beck O., Nayef R., Heo G.Y., Björkhem-Bergman L. et al. . (2010) The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo. J. Lipid. Res. 51, 318–323 10.1194/jlr.M900174-JLR200
    1. Mast N., Li Y., Linger M., Clark M., Wiseman J. and Pikuleva I.A. (2014) Pharmacologic Stimulation of Cytochrome P450 46A1 and Cerebral Cholesterol Turnover in Mice. J. Biol. Chem. 289, 3529–3538 10.1074/jbc.M113.532846
    1. Mast N., Linger M., Clark M., Wiseman J., Stout C.D. and Pikuleva I.A. (2012) In silico and intuitive predictions of CYP46A1 inhibition by marketed drugs with subsequent enzyme crystallization in complex with fluvoxamine. Mol. Pharmacol. 82, 824–834 10.1124/mol.112.080424
    1. Radhakrishnan A., Ikeda Y., Hyock J.K., Brown M.S. and Goldstein J.L. (2007) Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig. Proc. Natl. Acad. Sci. U.S.A. 104, 6511–6518 10.1073/pnas.0700899104
    1. Radhakrishnan A., Sun L.P., Kwon H.J., Brown M.S. and Goldstein J.L. (2004) Direct binding of cholesterol to the purified membrane region of SCAP: Mechanism for a sterol-sensing domain. Mol. Cell 15, 259–268 10.1016/j.molcel.2004.06.019
    1. Fourgeux C., Martine L., Acar N., Bron A.M., Creuzot-Garcher C.P. and Bretillon L. (2014) In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina. Biochem. Biophys. Res. Commun. 446, 775–781 10.1016/j.bbrc.2014.01.118
    1. Park K. and Scott A.L. (2010) Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons. J. Leukoc. Biol. 88, 1081–1087 10.1189/jlb.0610318
    1. Diczfalusy U., Olofsson K.E., Carlsson A.-M., Gong M., Golenbock D.T., Rooyackers O. et al. . (2009) Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide. J. Lipid. Res. 50, 2258–2264 10.1194/jlr.M900107-JLR200
    1. Gold E.S., Diercks A.H., Podolsky I., Podyminogin R.L., Askovich P.S., Treuting P.M. et al. . (2014) 25-Hydroxycholesterol acts as an amplifier of inflammatory signaling. Proc. Natl. Acad. Sci. U.S.A. 111, 10666–10671 10.1073/pnas.1404271111
    1. Blanc M., Hsieh W.Y., Robertson K.A., Kropp K.A., Forster T., Shui G. et al. . (2013) The Transcription Factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38, 106–118 10.1016/j.immuni.2012.11.004
    1. Liu S.-Y., Aliyari R., Chikere K., Li G., Marsden M.D., Smith J.K. et al. . (2013) Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol. Immunity 38, 92–105 10.1016/j.immuni.2012.11.005
    1. Jang J., Park S., Jin Hur H., Cho H.-J., Hwang I., Pyo Kang Y. et al. . (2016) 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat. Commun. 7, 13129 10.1038/ncomms13129
    1. Okabe A., Urano Y., Itoh S., Suda N., Kotani R., Nishimura Y. et al. . (2014) Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death. Redox Biol. 2, 28–35 10.1016/j.redox.2013.11.007
    1. Meaney S., Bodin K., Diczfalusy U. and Björkhem I. (2002) On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function. J. Lipid. Res. 43, 2130–2135 10.1194/jlr.M200293-JLR200
    1. Ohtsuki S., Ito S., Matsuda A., Hori S., Abe T. and Terasaki T. (2007) Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier. J. Neurochem. 103, 1430–1438 10.1111/j.1471-4159.2007.04901.x
    1. Yatin S.M., Varadarajan S. and Butterfield D.A. (2000) Vitamin E Prevents Alzheimer’s Amyloid ß-Peptide (1-42)-Induced Neuronal Protein Oxidation and Reactive Oxygen Species Production. J. Alzheimer’s Dis. 2, 123–131 10.3233/JAD-2000-2212
    1. Schilling T. and Eder C. (2011) Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J. Cell Physiol. 226, 3295–3302 10.1002/jcp.22675
    1. Yan S.D., Chen X., Fu J., Chen M., Zhu H., Roher A. et al. . (1996) RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691 10.1038/382685a0
    1. Urrutia P.J., Hirsch E.C., González-Billault C. and Núñez M.T. (2017) Hepcidin attenuates amyloid beta-induced inflammatory and pro-oxidant responses in astrocytes and microglia. J. Neurochem. 142, 140–152 10.1111/jnc.14005
    1. Subbarao K.V., Richardson J.S. and Ang L.C. (1990) Autopsy Samples of Alzheimer’s Cortex Show Increased Peroxidation In Vitro. J. Neurochem. 55, 342–345 10.1111/j.1471-4159.1990.tb08858.x
    1. Markesbery W. and Lovell M. (1998) Four-Hydroxynonenal, a Product of Lipid Peroxidation, is Increased in the Brain in Alzheimer’s Disease. Neurobiol. Aging 19, 33–36 10.1016/S0197-4580(98)00009-8
    1. Saharan S. and Mandal P.K. (2014) The emerging role of glutathione in Alzheimer’s disease. J. Alzheimer’s Dis. 40, 519–529 10.3233/JAD-132483
    1. Mandal P.K., Saharan S., Tripathi M. and Murari G. (2015) Brain glutathione levels - a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol. Psychiatry 78, 702–710 10.1016/j.biopsych.2015.04.005
    1. Testa G., Staurenghi E., Zerbinati C., Gargiulo S., Iuliano L., Giaccone G. et al. . (2016) Changes in brain oxysterols at different stages of Alzheimer’s disease: Their involvement in neuroinflammation. Redox Biol. 10, 24–33 10.1016/j.redox.2016.09.001
    1. Liang Q., Liu H., Zhang T., Jiang Y., Xing H. and Zhang A. (2016) Discovery of serum metabolites for diagnosis of progression of mild cognitive impairment to Alzheimer’s disease using an optimized metabolomics method. RSC Adv. 6, 3586–3591 10.1039/C5RA19349D
    1. Raza H., John A. and Howarth F.C. (2015) Increased oxidative stress and mitochondrial dysfunction in Zucker diabetic rat liver and brain. Cell Physiol. Biochem. 35, 1241–1251 10.1159/000373947
    1. Sözbir E. and Nazıroğlu M. (2016) Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain. Metab. Brain Dis. 31, 385–393 10.1007/s11011-015-9769-7
    1. Cavaliere G., Viggiano E., Trinchese G., De Filippo C., Messina A., Monda V. et al. . (2018) Long Feeding High-Fat Diet Induces Hypothalamic Oxidative Stress and Inflammation, and Prolonged Hypothalamic AMPK Activation in Rat Animal Model. Front Physiol. 9, 818 10.3389/fphys.2018.00818
    1. Alzoubi K.H., Mayyas F.A., Mahafzah R. and Khabour O.F. (2018) Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. Behav. Brain Res. 336, 93–98 10.1016/j.bbr.2017.08.047
    1. Romano S., Mitro N., Giatti S., Diviccaro S., Pesaresi M., Spezzano R. et al. . (2018) Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex. J. Steroid. Biochem. Mol. Biol. 178, 108–116 10.1016/j.jsbmb.2017.11.009
    1. Romano S., Mitro N., Diviccaro S., Spezzano R., Audano M., Garcia-Segura L.M. et al. . (2017) Short-term effects of diabetes on neurosteroidogenesis in the rat hippocampus. J. Steroid. Biochem. Mol. Biol. 167, 135–143 10.1016/j.jsbmb.2016.11.019
    1. Endo K., Oyama T., Saiki A., Ban N., Ohira M., Koide N. et al. . (2008) Determination of serum 7-ketocholesterol concentrations and their relationships with coronary multiple risks in diabetes mellitus. Diabetes Res. Clin. Pract. 80, 63–68 10.1016/j.diabres.2007.10.023
    1. Samadi A., Gurlek A., Sendur S.N., Karahan S., Akbiyik F. and Lay I. (2019) Oxysterol species: reliable markers of oxidative stress in diabetes mellitus. J. Endocrinol. Invest. 42, 7–17 10.1007/s40618-018-0873-5
    1. Ferderbar S., Pereira E.C., Apolinário E., Bertolami M.C., Faludi A., Monte O. et al. . (2007) Cholesterol oxides as biomarkers of oxidative stress in type 1 and type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 23, 35–42 10.1002/dmrr.645
    1. Wang H.-L., Wang Y.-Y., Liu X.-G., Kuo S.-H., Liu N., Song Q.-Y. et al. . (2016) Cholesterol, 24-Hydroxycholesterol, and 27-hydroxycholesterol as surrogate biomarkers in cerebrospinal fluid in mild cognitive impairment and alzheimer’s disease: a meta-analysis. J. Alzheimer’s Dis. 51, 45–55 10.3233/JAD-150734
    1. 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 10.1016/j.neulet.2004.07.031
    1. Benussi L., Ghidoni R., Dal Piaz F., Binetti G., Di Iorio G. and Abrescia P. (2017) The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer’s Disease. J. Alzheimer’s Dis. 56, 825–833 10.3233/JAD-160930
    1. 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 10.1194/jlr.M300320-JLR200
    1. Murakami H., Tamasawa N., Matsui J., Yasujima M. and Suda T. (2000) Plasma oxysterols and tocopherol in patients with diabetes mellitus and hyperlipidemia. Lipids 35, 333–338 10.1007/s11745-000-0530-1
    1. Thelen K.M., Falkai P., Bayer T.A. and Lütjohann D. (2006) Cholesterol synthesis rate in human hippocampus declines with aging. Neurosci. Lett. 403, 15–19 10.1016/j.neulet.2006.04.034
    1. Boisvert M.M., Erikson G.A., Shokhirev M.N. and Allen N.J. (2018) The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Rep. 22, 269–285 10.1016/j.celrep.2017.12.039
    1. Svennerholm L., Boström K., Jungbjer B. and Olsson L. (1994) Membrane Lipids of Adult Human Brain: Lipid Composition of Frontal and Temporal Lobe in Subjects of Age 20 to 100 Years. J. Neurochem. 63, 1802–1811 10.1046/j.1471-4159.1994.63051802.x
    1. Palozza P., Simone R., Catalano A., Boninsegna A., Böhm V., Fröhlich K. et al. . (2010) Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. J. Nutr. Biochem. 21, 34–46 10.1016/j.jnutbio.2008.10.002
    1. Nury T., Zarrouk A., Vejux A., Doria M., Riedinger J.M., Delage-Mourroux R. et al. . (2014) Induction of oxiapoptophagy, a mixed mode of cell death associated with oxidative stress, apoptosis and autophagy, on 7-ketocholesterol-treated 158N murine oligodendrocytes: Impairment by α-tocopherol. Biochem. Biophys. Res. Commun. 446, 714–719 10.1016/j.bbrc.2013.11.081
    1. Leonarduzzi G., Vizio B., Sottero B., Verde V., Gamba P., Mascia C. et al. . (2006) Early Involvement of ROS Overproduction in Apoptosis Induced by 7-Ketocholesterol. Antioxid. Redox Signal. 8, 375–380 10.1089/ars.2006.8.375
    1. Testa G., Staurenghi E., Giannelli S., Gargiulo S., Guglielmotto M., Tabaton M. et al. . (2018) A silver lining for 24-hydroxycholesterol in Alzheimer’s disease: The involvement of the neuroprotective enzyme sirtuin 1. Redox Biol. 17, 423–431 10.1016/j.redox.2018.05.009
    1. Fu D., Wu M., Zhang J., Du M., Yang S., Hammad S.M. et al. . (2012) Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Diabetologia 55, 3128–3140 10.1007/s00125-012-2692-0
    1. Guillemot-Legris O. and Muccioli G.G. (2017) Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci. 40, 237–253 10.1016/j.tins.2017.02.005
    1. Noronha S.S.R., Lima P.M., Campos G.S.V., Chírico M.T.T., Abreu A.R., Figueiredo A.B. et al. . (2019) Association of high-fat diet with neuroinflammation, anxiety-like defensive behavioral responses, and altered thermoregulatory responses in male rats. Brain Behav. Immun. 80, 500–511 10.1016/j.bbi.2019.04.030
    1. Spencer S.J., D’Angelo H., Soch A., Watkins L.R., Maier S.F. and Barrientos R.M. (2017) High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. Neurobiol. Aging 58, 88–101 10.1016/j.neurobiolaging.2017.06.014
    1. Huang J.-D., Amaral J., Lee J.W. and Rodriguez I.R. (2014) 7-Ketocholesterol-Induced Inflammation Signals Mostly through the TLR4 Receptor Both In Vitro and In Vivo. Khoury J. El., editor. PLoS One 9, e100985 10.1371/journal.pone.0100985
    1. Ginhoux F., Lim S., Hoeffel G., Low D. and Huber T. (2013) Origin and differentiation of microglia. Front. Cell Neurosci. 7, 45 10.3389/fncel.2013.00045
    1. Colonna M. and Butovsky O. (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 10.1146/annurev-immunol-051116-052358
    1. Hansen D V., Hanson J.E. and Sheng M. (2018) Microglia in Alzheimer’s disease. J. Cell Biol. 217, 459–472 10.1083/jcb.201709069
    1. Pottier C., Wallon D., Rousseau S., Rovelet-Lecrux A., Richard A.-C., Rollin-Sillaire A. et al. . (2013) TREM2 R47H variant as a risk factor for early-onset Alzheimer’s disease. J. Alzheimers Dis. 35, 45–49 10.3233/JAD-122311
    1. Jonsson T., Stefansson H., Steinberg S., Jonsdottir I., Jonsson P V., Snaedal J. et al. . (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 10.1056/NEJMoa1211103
    1. Baufeld C., Osterloh A., Prokop S., Miller K.R. and Heppner F.L. (2016) High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol. 132, 361–375 10.1007/s00401-016-1595-4
    1. Valdearcos M., Douglass J.D., Robblee M.M., Dorfman M.D., Stifler D.R., Bennett M.L. et al. . (2017) Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 26, 185.e3–197.e3 10.1016/j.cmet.2017.05.015
    1. Spangenberg E., Severson P.L., Hohsfield L.A., Crapser J., Zhang J., Burton E.A. et al. . (2019) Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat. Commun. 10, 3758 10.1038/s41467-019-11674-z
    1. Sosna J., Philipp S., Albay R. III, Reyes-Ruiz J.M., Baglietto-Vargas D., LaFerla F.M. et al. . (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol. Neurodegener. 13, 11 10.1186/s13024-018-0244-x
    1. Chistiakov D.A., Bobryshev Y V. and Orekhov A.N. (2016) Macrophage-mediated cholesterol handling in atherosclerosis. J. Cell. Mol. Med. 20, 17–28 10.1111/jcmm.12689
    1. Chang J.Y., Chavis J.A., Liu L.Z. and Drew P.D. (1998) Cholesterol oxides induce programmed cell death in microglial cells. Biochem. Biophys. Res. Commun. 249, 817–821 10.1006/bbrc.1998.9237
    1. Chang J.Y. and Liu L.Z. (2001) Peroxisome proliferator-activated receptor agonists prevent 25-OH-cholesterol induced c-jun activation and cell death. BMC Pharmacol. 1, 10 10.1186/1471-2210-1-10
    1. Diestel A., Aktas O., Hackel D., Hake I., Meier S., Raine C.S. et al. . (2003) Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J. Exp. Med. 198, 1729–1740 10.1084/jem.20030975
    1. Rosado M.M., Bennici E., Novelli F. and Pioli C. (2013) Beyond DNA repair, the immunological role of PARP-1 and its siblings. Immunology 139, 428–437 10.1111/imm.12099
    1. Farez M.F., Quintana F.J., Gandhi R., Izquierdo G., Lucas M. and Weiner H.L. (2009) Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat. Immunol. 10, 958–964 10.1038/ni.1775
    1. Liu S., Liu Y., Hao W., Wolf L., Kiliaan A.J., Penke B. et al. . (2012) TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J. Immunol. 188, 1098–1107 10.4049/jimmunol.1101121
    1. Kauppinen T.M., Suh S.W., Higashi Y., Berman A.E., Escartin C., Won S.J. et al. . (2011) Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid beta. J Neuroinflammation 8, 152 10.1186/1742-2094-8-152
    1. Indaram M., Ma W., Zhao L., Fariss R.N., Rodriguez I.R. and Wong W.T. (2015) 7-ketocholesterol increases retinal microglial migration, activation and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration. Sci. Rep. 5, 9144 10.1038/srep09144
    1. Shi G., Chen S., Wandu W.S., Ogbeifun O., Nugent L.F., Maminishkis A. et al. . (2015) Inflammasomes Induced by 7-Ketocholesterol and Other Stimuli in RPE and in Bone Marrow-Derived Cells Differ Markedly in Their Production of IL-1beta and IL-18. Invest. Ophthalmol. Vis. Sci. 56, 1658–1664 10.1167/iovs.14-14557
    1. Mutemberezi V., Buisseret B., Masquelier J., Guillemot-Legris O., Alhouayek M. and Muccioli G.G. (2018) Oxysterol levels and metabolism in the course of neuroinflammation: insights from in vitro and in vivo models. J. Neuroinflammation 15, 74 10.1186/s12974-018-1114-8

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren