Abstract
Dementia is a syndrome characterized by deterioration in memory, behavior, and the ability to perform everyday activities. Currently available drugs have no impact on progression and do not offer a cure, so identifying and studying new therapeutic approaches is important. There is evidence that indicates disturbances in cholesterol homeostasis can be related to dementia. The present chapter aims to address the relationship that exists between the metabolism of cholesterol and dementia, especially in Alzheimer’s disease and vascular dementia, and how this relationship has been used for therapeutic purposes, from the use of statins to the development of new drugs, such as ACAT inhibitors, highlighting the importance of cholesterol in the proper functioning of the brain and how this can represent a useful path for designing new therapeutic approaches.
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References
Alzheimer A (1906) Über einen eigenartigen schweren Erkrankungsprozeß der Hirnrinde. Neurol Zentralblatt 23:1129–1136
Antalis CJ, Arnold T, Rasool T et al (2010) High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat 122:661–670. https://doi.org/10.1007/s10549-009-0594-8
Appleton JP, Scutt P, Sprigg N, Bath PM (2017) Hypercholesterolaemia and vascular dementia. Clin Sci 131:1561–1578. https://doi.org/10.1042/CS20160382
Araki W, Tamaoka A (2015) Amyloid beta-protein and lipid rafts: focused on biogenesis and catabolism. Front Biosci 20:314–324. https://doi.org/10.2741/4311
Area-Gomez E, Lara M, Tambini MD et al (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31:4106–4123. https://doi.org/10.1038/emboj.2012.202
Arenas F, Garcia-Ruiz C, Fernandez-Checa JC (2017) Intracellular cholesterol trafficking and impact in neurodegeneration. Front Mol Neurosci 10:382. https://doi.org/10.3389/fnmol.2017.00382
Arvanitakis Z, Schneider J, Wilson R et al (2008) Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 70:1795–1802
Attems J, Jellinger KA (2014) The overlap between vascular disease and Alzheimer’s disease – lessons from pathology. BMC Med 12:1–12
Bemlih S, Poirier MD, El Andaloussi A (2010) Acyl-coenzyme A: Cholesterol acyltransferase inhibitor avasimibe affect survival and proliferation of glioma tumor cell lines. Cancer Biol Ther 9:1025–1032. https://doi.org/10.4161/cbt.9.12.11875
Bertram L, Hsiao M, Mullin K et al (2005) ACAT1 is not associated with Alzheimer’s disease in two independent family-based samples. Mol Psychiatry 10:522–524. https://doi.org/10.1038/sj.mp.4001646
Bhattacharyya R, Kovacs DM (2010) ACAT inhibition and amyloid beta reduction. Biochim Biophys Acta 1801:960–965. https://doi.org/10.1016/j.bbalip.2010.04.003
Bitzur R (2016) Remembering statins: do statins have adverse cognitive effects? Diabetes Care 39:253–259. https://doi.org/10.2337/dcS15-3022
Björkhem I, Meaney S, Fogelman AM (2004) Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24:806–815. https://doi.org/10.1161/01.ATV.0000120374.59826.1b
Bocan TM, Mueller SB, Uhlendorf PD et al (1991) Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in iliac-femoral and thoracic aortic lesions. A biochemical, morphological, and morphometric evaluation. Arterioscler Thromb 11:1830–1843
Bogdanovic N, Bretillon L, Lund EG 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. https://doi.org/10.1016/S0304-3940(01)02277-7
Boimel M, Grigoriadis N, Lourbopoulos A et al (2009) Statins reduce the neurofibrillary tangle burden in a mouse model of tauopathy. J Neuropathol Exp Neurol 68:314–325. https://doi.org/10.1097/NEN.0b013e31819ac3cb
Bolós M, Llorens-Martín M, Jurado-Arjona J et al (2016) Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis 50:77–87. https://doi.org/10.3233/JAD-150704
Bryleva EY, Rogers MA, Chang CCY et al (2010) ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc Natl Acad Sci 107:3081–3086. https://doi.org/10.1073/pnas.0913828107
Burlot MA, Braudeau J, Michaelsen-Preusse K et al (2015) Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology. Hum Mol Genet 24:5965–5976. https://doi.org/10.1093/hmg/ddv268
Caccamo A, Majumder S, Richardson A et al (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J Biol Chem 285:13107–13120. https://doi.org/10.1074/jbc.M110.100420
Canevari L, Clark JB (2007) Alzheimer’s disease and cholesterol: the fat connection. Neurochem Res 32:739–750. https://doi.org/10.1007/s11064-006-9200-1
Chan RB, Oliveira TG, Cortes EP et al (2012) Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 287:2678–2688. https://doi.org/10.1074/jbc.M111.274142
Chang CCY, Chen J, Thomas M et al (1995) Regulation and immunolocalization of acyl-coenzyme A:cholesterol acyltransferase in mammalian cells as studied with specific antibodies. J Biol Chem 270:29532–29540. https://doi.org/10.1074/jbc.270.49.29532
Chen Y, Zhu L, Ji L et al (2018) Silencing the ACAT1 gene in human SH-SY5Y neuroblastoma cells inhibits the expression of cyclo-oxygenase 2 (COX2) and reduces β-amyloid-induced toxicity due to activation of protein kinase C (PKC) and ERK. Med Sci Monit 24:9007–9018. https://doi.org/10.12659/msm.912862
Chen H, Du Y, Liu S et al (2019) Association between serum cholesterol levels and Alzheimer’s disease in China: a case-control study. Int J Food Sci Nutr 70:405–411. https://doi.org/10.1080/09637486.2018.1508426
Cingolani F, Czaja MJ (2017) Regulation and functions of autophagic lipolysis. Trends Endocrinol Metab 27:696–705. https://doi.org/10.1016/j.tem.2016.06.003.Regulation
Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of Apolipoprotein E type 4 allele and risk of Alzheimer’s disease in late onset families. Science 261:921–923
Cordy JM, Hooper NM, Turner AJ (2006) The involvement of lipid rafts in Alzheimer’s disease. Mol Membr Biol 23:111–122. https://doi.org/10.1080/09687860500496417
Cossec JC, Simon A, Marquer C et al (2010) Clathrin-dependent APP endocytosis and Aβ secretion are highly sensitive to the level of plasma membrane cholesterol. Biochim Biophys Acta Mol Cell Biol Lipids 1801:846–852. https://doi.org/10.1016/j.bbalip.2010.05.010
Cramer C, Haan MN, Galea S et al (2008) Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 71:344–350. https://doi.org/10.1212/01.wnl.0000319647.15752.7b
Daneschvar HL, Aronson MD, Smetana GW (2015) Do statins prevent Alzheimer’s disease? A narrative review. Eur J Int Med 26:666–669. https://doi.org/10.1016/j.ejim.2015.08.012
Di Paolo G, Kim T (2012) Linking Lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296. https://doi.org/10.1038/nrn3012.Linking
Dickson J, Kruse C, Montagna DR et al (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127:1–7. https://doi.org/10.1038/jid.2014.371
Dietschy JM (2009) Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390:287–293. https://doi.org/10.1515/BC.2009.035
Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12:105–112. https://doi.org/10.1194/jlr.r400004-jlr200
van Dijk EJ, Prins ND, Vrooman HA et al (2008) Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam scan study. Stroke 39:2712–2719. https://doi.org/10.1161/STROKEAHA.107.513176
Eckert GP, Wood WG, Müller WE (2001) Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J Neural Transm 108:1051–1064. https://doi.org/10.1007/s007020170024
Fassbender K, Simons M, Bergmann C et al (2001) Simvastatin strongly reduces levels of Alzheimer’s disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. PNAS 98:5856–5861
FDA (2012) Drug safety communication: important safety label changes to cholesterol-lowering statin drugs. In: FDA Consum. Heal. Inf., Expand. Advice statin risks. FDA, Rome. www.fda.gov/consumer
Geng F, Guo D (2017) Lipid droplets, potential biomarker and metabolic target in glioblastoma. Int Med Rev 3:1–9
Geng F, Cheng X, Wu X et al (2017) Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin Cancer Res 22:5337–5348. https://doi.org/10.1158/1078-0432.CCR-15-2973.Inhibition
Glöckner F, Ohm TG (2014) Tau pathology induces intraneuronal cholesterol accumulation. J Neuropathol Exp Neurol 73:846–854. https://doi.org/10.1097/NEN.0000000000000103
Glöckner F, Meske V, Lütjohann D, Ohm TG (2011) Dietary cholesterol and its effect on tau protein: a study in apolipoprotein e-deficient and P301L human tau mice. J Neuropathol Exp Neurol 70:292–301. https://doi.org/10.1097/NEN.0b013e318212f185
Gouw AA, van der Flier WM, Fazekas F et al (2008) Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the leukoaraiosis and disability study. Stroke 39:1414–1420. https://doi.org/10.1161/STROKEAHA.107.498535
Gratuze M, Julien J, Morin F et al (2016) High-fat, high-sugar, and high-cholesterol consumption does not impact tau pathogenesis in a mouse model of Alzheimer’s disease-like tau pathology. Neurobiol Aging 47:71–73. https://doi.org/10.1016/j.neurobiolaging.2016.07.016
Griciuc A, Serrano A, Parrado AR et al (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643. https://doi.org/10.1016/j.neuron.2013.04.014.Alzheimer
Haag MDM, Hofman A, Koudstaal PJ et al (2009) Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam study. J Neurol Neurosurg Psychiatry 80:13–17. https://doi.org/10.1136/jnnp.2008.150433
Hainer JW, Terry JG, Connell JM et al (1994) Effect of the acyl-CoA: cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Clin Pharmacol Ther 56:65–74. https://doi.org/10.1038/clpt.1994.102
Hall JR, Wiechmann AR, Johnson LA et al (2014) Total cholesterol and neuropsychiatric symptoms in Alzheimer’s disease: the impact of total cholesterol level and gender. Dement Geriatr Cogn Disord 38:300–309. https://doi.org/10.1159/000361043
Hardy J, Higgins G (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185. https://doi.org/10.1177/875512250001600415
Hickman SE, Allison EK, Khoury J (2008) Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28:8354–8360. https://doi.org/10.1523/JNEUROSCI.0616-08.2008.Microglial
Holtzman DM, Morris JC, Goate A (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:1–35. https://doi.org/10.1126/scitranslmed.3002369.Alzheimer
Hopp SC, Lin Y, Oakley D et al (2018) The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J Neuroinflammation 15:1–15. https://doi.org/10.1186/s12974-018-1309-z
Hussain G, Wang J, Rasul A et al (2019) Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids Health Dis 18:1–12
Hutter-Paier B, Huttunen HJ, Puglielli L et al (2004) The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron 44:227–238. https://doi.org/10.1016/j.neuron.2004.08.043
Huttunen HJ, Greco C, Kovacs DM (2007) Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS Lett 581:1688–1692. https://doi.org/10.1016/j.febslet.2007.03.056
Huttunen HJ, Peach C, Bhattacharyya R et al (2009) Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. FASEB J 23:3819–3828. https://doi.org/10.1096/fj.09-134999
Huttunen HJ, Havas D, Peach C et al (2010) The acyl-coenzyme A:cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice. J Neuropathol Exp Neurol 69:777–788. https://doi.org/10.1097/NEN.0b013e3181e77ed9.The
Ikram MA, Bersano A, Manso R et al (2017) Genetics of vascular dementia – review from the ICVD working group. BMC Med 15:1–7. https://doi.org/10.1186/s12916-017-0813-9
Jick H, Zornberg GL, Jick SS et al (2000) Statins and the risk of dementia. Lancet 356:1627–1631
Kalaria RN (2016) Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathol 131:659–685. https://doi.org/10.1007/s00401-016-1571-z
van der Kant R, Langness VF, Herrera CM 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 24:363–375. https://doi.org/10.1016/j.stem.2018.12.013
van der Kant R, Goldstein LSB, Ossenkoppele R (2020) Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci 21:21–35. https://doi.org/10.1038/s41583-019-0240-3
Kapasi A, Schneider JA (2016) Vascular contributions to cognitive impairment, clinical Alzheimer’s disease, and dementia in older persons. Biochim Biophys Acta 1862:878–886. https://doi.org/10.1016/j.bbadis.2015.12.023
Khan A, Corbett A, Ballard C (2017) Emerging amyloid and tau targeting treatments for Alzheimer’s disease. Expert Rev Neurother 17:697–711. https://doi.org/10.1080/14737175.2017.1326819
Kim LD, Factora RM (2018) Alzheimer dementia: starting, stopping drug therapy. Cleve Clin J Med 85:209–214. https://doi.org/10.3949/ccjm.85a.16080
Kim Y, Kim C, Jang HY, Mook-Jung I (2016) Inhibition of cholesterol biosynthesis reduces γ-secretase activity and amyloid-β generation. J Alzheimers Dis 51:1057–1068. https://doi.org/10.3233/JAD-150982
Kinno R, Mori Y, Kubota S et al (2019) High serum high-density lipoprotein-cholesterol is associated with memory function and gyrification of insular and frontal opercular cortex in an elderly memory-clinic population. NeuroImage Clin 22:1–9. https://doi.org/10.1016/j.nicl.2019.101746
Kivipelto M, Helkala EL, Hänninen T et al (2001) Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56:1683–1689. https://doi.org/10.1212/WNL.56.12.1683
Koldamova R, Fitz NF, Lefterov I (2010) The role of ATP-binding cassette transporter A1 in Alzheimer’s disease and neurodegeneration. Biochim Biophys Acta 1801:824–830. https://doi.org/10.1016/j.bbalip.2010.02.010.The
Lämsä R, Helisalmi S, Herukka SK et al (2007) Study on the association between SOAT1 polymorphisms, Alzheimer’s disease risk and the level of CSF biomarkers. Dement Geriatr Cogn Disord 24:146–150. https://doi.org/10.1159/000105164
Lee HT, Sliskovic DR, Picard JA et al (1996) Inhibitors of Acyl-CoA:cholesterol O-Acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: an acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets. J Med Chem 39:5031–5034. https://doi.org/10.1021/jm960674d
Lee SSY, Li J, Tai JN et al (2015) Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment. ACS Nano 9:2420–2432. https://doi.org/10.1021/nn504025a
Leoni V, Solomon A, Kivipelto M (2010) Links between ApoE, brain cholesterol metabolism, tau and amyloid β-peptide in patients with cognitive impairment. Biochem Soc Trans 38:1021–1025. https://doi.org/10.1042/BST0381021
Leritz EC, Mcglinchey RE, Salat DH, Milberg WP (2016) Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory. Metab Brain Dis 31:465–473. https://doi.org/10.1007/s11011-016-9797-y.Elevated
Li J, Gu D, Lee SSY et al (2016) Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 35:6378–6388. https://doi.org/10.1038/onc.2016.168
Li G, Mayer CL, Morelli D et al (2017) Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults. Neurology 89:1251–1255. https://doi.org/10.1212/WNL.0000000000004392
Liu L, Zhang K, Sandoval H et al (2015) Glial lipid drolets and ROS induced by mitochondrial defects promote neurodegeneration. Cell 160:177–190. https://doi.org/10.1016/j.cell.2014.12.019.Glial
Liu Q, An Y, Ma W et al (2018) High-cholesterol diet results in elevated amyloid-β and oxysterols in rats. Mol Med Rep 17:1235–1240. https://doi.org/10.3892/mmr.2017.8003
Llaverias G, Alegret M (2004) Inhibidores de la acil coenzima A:colesterol aciltransferasa (ACAT): mecanismos y perspectivas terapéuticas. Clin Invest Arter 16:250–261. https://doi.org/10.1016/S0214-9168(04)79002-6
Longstreth WT, Arnold AM, Beauchamp NJ et al (2005) Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance: the cardiovascular health study. Stroke 36:56–61. https://doi.org/10.1161/01.STR.0000149625.99732.69
Lund EG, Xie C, Kotti T et al (2003) Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem 278:22980–22988. https://doi.org/10.1074/jbc.M303415200
Luo W, Liu W, Hu X et al (2015) Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep 5:1–12. https://doi.org/10.1038/srep11161
Lütjohann D, von Bergmann K (2003) 24S-hydroxycholesterol: a marker of brain cholesterol metabolism. Pharmacopsychiatry 36:102–106. https://doi.org/10.1055/s-2003-43053
Lütjohann D, Meichsner S, Pettersson H (2012) Lipids in Alzheimer’s disease and their potential for therapy. Clin Lipidol 7:65–78. https://doi.org/10.2217/clp.11.74
Marcum ZA, Walker R, Bobb JF et al (2018) Serum cholesterol and incident Alzheimer’s disease: findings from the adult changes in thought study. J Am Geriatr Soc 66:2344–2352. https://doi.org/10.1111/jgs.15581.Serum
Martin MG, Pfrieger F, Dotti CG (2014) Cholesterol in brain disease: sometimes determinant and frequently implicated. EMBO Rep 15:1036–1052. https://doi.org/10.15252/embr.201439225
Mast N, Saadane A, Valencia-olvera A et al (2017) Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer’s disease. Neuropharmacology 123:465–476. https://doi.org/10.1016/j.neuropharm.2017.06.026.Cholesterol-Metabolizing
Maulik M, Westaway D, Jhamandas JH, Kar S (2013) Role of cholesterol in APP metabolism and its significance in Alzheimer’s disease pathogenesis. Mol Neurobiol 47:37–63. https://doi.org/10.1007/s12035-012-8337-y
Mcguinness B, Craig D, Bullock R et al (2014) Statins for the treatment of dementia. Cochrane Database Syst Rev (7):CD007514
Mcguinness B, Craig D, Bullock R, Passmore P (2016) Statins for the prevention of dementia. Cochrane Database Syst Rev (1):CD003160. https://doi.org/10.1002/14651858.CD003160.pub3. www.cochranelibrary.com
Meuwese M, Groot E, Duivenvoorden R et al (2009) ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia. JAMA 301:1131–1139
Mielke M, Zandi P, Sjögren M et al (2005) High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 64:1689–1695
Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873. https://doi.org/10.1101/gad.1599207
Moutinho M, Nunes MJ, Rodrigues E (2016) Cholesterol 24-hydroxylase: brain cholesterol metabolism and beyond. Biochim Biophys Acta Mol Cell Biol Lipids 1861:1911–1920. https://doi.org/10.1016/j.bbalip.2016.09.011
Murphy SR, Chang CCY, Dogbevia G et al (2013) Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer’s disease. Mol Ther 21:1497–1506. https://doi.org/10.1038/mt.2013.118
Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV (2016) Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta 1862:887–900. https://doi.org/10.1016/j.bbadis.2015.12.016.Neurovascular
Nicholls SJ, Sipahi I, Schoenhagen P et al (2006) Intravascular ultrasound assessment of novel antiatherosclerotic therapies: rationale and design of the Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Study. Am Heart J 152:67–74. https://doi.org/10.1016/j.ahj.2005.10.025
Nissen SE, Tardif J-C, Nicholls SJ et al (2006) Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 354:1253–1263. https://doi.org/10.1056/NEJMoa070635
Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243. https://doi.org/10.1161/CIRCRESAHA.116.308537
Panza F, D’Introno A, Colacicco AM et al (2006) Lipid metabolism in cognitive decline and dementia. Brain Res Rev 51:275–292. https://doi.org/10.1016/j.brainresrev.2005.11.007
Pappolla MA, Bryant-Thomas TK, Herbert D et al (2003) Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61:199–205. https://doi.org/10.1212/01.WNL.0000070182.02537.84
Pennetta G, Welte M (2019) Emerging links between lipid droplets and motor neuron diseases. Dev Cell 45:427–432. https://doi.org/10.1016/j.devcel.2018.05.002.Emerging
Perea JR, Llorens-Martín M, Ávila J, Bolós M (2018) The role of microglia in the spread of Tau: relevance for tauopathies. Front Cell Neurosci 12:1–8. https://doi.org/10.3389/fncel.2018.00172
Petrov AM, Kasimov MR, Zefirov AL (2016) Brain cholesterol metabolism and its defects: linkage to neurodegenerative diseases and synaptic dysfunction. Acta Nat 8:58–73
Posse E (2012) Reciprocal regulation of cholesterol and beta amyloid at the subcellular level in Alzheimer’s disease. Can J Physiol Pharmacol 90:753–764. https://doi.org/10.1139/y2012-076
Provenzano FA, Muraskin J, Tosto G et al (2013) White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease? JAMA Neurol 70:455–461. https://doi.org/10.1001/jamaneurol.2013.1321
Puglielli L, Konopka G, Pack-Chung E et al (2001) Acyl-coenzyme A: Cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol 3:905–912. https://doi.org/10.1038/ncb1001-905
Refolo LM, Pappolla MA, Malester B et al (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7:321–331. https://doi.org/10.1006/nbdi.2000.0304
Riekse RG, Li G, Petrie EC et al (2006) Effect of statins on Alzheimer’s disease biomarkers in cerebrospinal fluid. J Alzheimers Dis 10:399–406. https://doi.org/10.3233/JAD-2006-10408
Rockwood K, Kirkland S, Hogan DB et al (2002) Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59:223–227. https://doi.org/10.1001/archneur.59.2.223
Rogers MA, Liu J, Song B et al (2015) Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol 151:102–107. https://doi.org/10.1016/j.jsbmb.2014.09.008.Acyl-CoA
Rohilla A, Rohilla S, Kumar A et al (2011) Pleiotropic effects of statins: a boulevard to cardioprotection. Arab J Chem 9:21–27. https://doi.org/10.1016/j.arabjc.2011.06.025
Rohn TT (2014) Is apolipoprotein E4 an important risk factor for vascular dementia? Int J Clin Exp Pathol 7:3504–3511
Roth BD (1998) ACAT inhibitors: evolution from cholesterol-absorption inhibitors to antiatherosclerotic agents. Drug Discov Today 3:19–25
Saunders AM, Strittmatter WJ, Schmechel D et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472. https://doi.org/10.1212/WNL.43.8.1467
Saxena U (2009) Lipid metabolism and Alzheimer’s disease: pathways and possibilities. Expert Opin Ther Targets 13:331–338. https://doi.org/10.1517/14728220902738720
Schultz BG, Patten DK, Berlau DJ (2018) The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener 7:1–11. https://doi.org/10.1186/s40035-018-0110-3
Sepulcre J, Grothe MJ, d’Oleire Uquillas F et al (2018) Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat Med 24:1910–1918. https://doi.org/10.1038/s41591-018-0206-4
Settembre C, Di Malta C, Polito VA et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433. https://doi.org/10.1126/science.1204592.TFEB
Shabir O, Berwick J, Francis SE (2018) Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis. BMC Neurosci 19:1–16. https://doi.org/10.1186/s12868-018-0465-5
Shibuya Y, Chang CCY, Huang L-H et al (2014) Inhibiting ACAT1/SOAT1 in microglia stimulates autophagy-mediated lysosomal proteolysis and increases A 1-42 clearance. J Neurosci 34:14484–14501. https://doi.org/10.1523/JNEUROSCI.2567-14.2014
Shibuya Y, Chang CC, Chang T-Y (2015a) ACAT1/SOAT1 as a therapeutic target for Alzheimer’s disease. Future Med Chem 7:2451–2467. https://doi.org/10.4155/fmc.15.161
Shibuya Y, Niu Z, Bryleva EY et al (2015b) Acyl-CoA:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer’s disease mouse and reduces human P301L-tau content at the pre-symptomatic stage. Neurobiol Aging 36:2248–2259. https://doi.org/10.1016/j.neurobiolaging.2015.04.002.Acyl-CoA
Skrobot OA, McKnight AJ, Passmore PA et al (2016) A validation study of vascular cognitive impairment genetics meta-analysis findings in an independent collaborative cohort. J Alzheimers Dis 53:981–989. https://doi.org/10.3233/jad-150862
Sodhi RK, Singh N (2013) Liver X receptors: emerging therapeutic targets for Alzheimer’s disease. Pharmacol Res 72:45–51. https://doi.org/10.1016/j.phrs.2013.03.008
Solomon A, Kåreholt I, Ngandu T et al (2009a) Serum total cholesterol, statins and cognition in non-demented elderly. Neurobiol Aging 30:1006–1009. https://doi.org/10.1016/j.neurobiolaging.2007.09.012
Solomon A, Kivipelto M, Wolozin B et al (2009b) Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28:75–80. https://doi.org/10.1159/000231980
Sparks L, Kryscio RJ, Sabbagh MN et al (2008) Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res 5:416–421. https://doi.org/10.2174/156720508785132316
St Clair D, Rennie M, Slorach E et al (1995) Apolipoprotein E ε4 allele is a risk factor for familial and sporadic presenile Alzheimer’s disease in both homozygote and heterozygote carriers. J Med Genet 32:642–644. https://doi.org/10.1136/jmg.32.8.642
Strittmatter WJ, Saunders AM, Schmechel D et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci 90:1977–1981. https://doi.org/10.1073/pnas.90.5.1977
Suh Y-H (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54:469–525. https://doi.org/10.1124/pr.54.3.469
Suidan GL, Ramaswamy G (2019) Targeting apolipoprotein E for Alzheimer’s disease: an industry perspective. Int J Mol Sci 20:1–14
Sun JH, Tan L, Wang HF et al (2015a) Genetics of vascular dementia: systematic review and meta-analysis. J Alzheimers Dis 46:611–629. https://doi.org/10.3233/JAD-143102
Sun JH, Yu JT, Tan L (2015b) The role of cholesterol metabolism in Alzheimer’s disease. Mol Neurobiol 51:947–965. https://doi.org/10.1007/s12035-014-8749-y
Swiger KJ, Manalac RJ, Blumenthal RS et al (2013) Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 88:1213–1221. https://doi.org/10.1016/j.mayocp.2013.07.013
Szeto J, Lewis S (2016) Current treatment options for Alzheimer’s disease and Parkinson’s disease dementia. Curr Neuropharmacol 14:326–338. https://doi.org/10.2174/1570159X14666151208112754
Tajima Y, Ishikawa M, Maekawa K et al (2013) Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer’s disease. Lipids Health Dis 12:1–14
Tan B, Rosenfeldt F, Ou R et al (2019) Evidence and mechanisms for statin-induced cognitive decline. Expert Rev Clin Pharmacol 12:397–406. https://doi.org/10.1080/17512433.2019.1606711
Tardif JC, Grégoire J, L’Allier PL et al (2004) Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 110:3372–3377. https://doi.org/10.1161/01.CIR.0000147777.12010.EF
de la Torre J (2002) Alzheimer disease as a vascular disorder nosological. Stroke 33:1152–1162
Urano Y, Vo DH, Hirofumi A, Noguchi N (2019) 24 (S)-hydroxycholesterol induces ER dysfunction-mediated unconventional cell death. Cell Death Dis 5:113. https://doi.org/10.1038/s41420-019-0192-4
US National Library of Medicine (2009) ClinicalTrials.gov. In: Trial Simvastatin Amnestic Mild Cogn. Impair. Patients. https://clinicaltrials.gov/ct2/show/NCT00842920
Vetrivel KS, Thinakaran G (2006) Amyloidogenic processing of β-amyloid precursor protein in intracellular compartments. Neurology 66:S69–S73. https://doi.org/10.1212/01.wnl.0000192107.17175.39
Vijayan M, Reddy PH (2016) Stroke and vascular dementia and Alzheimer’s disease-molecular links. J Alzheimers Dis 54:427–443. https://doi.org/10.3233/JAD-160527.Stroke
Walker LC, Lynn DG, Chernoff YO (2018) A standard model of Alzheimer’s disease? Prion 12:261–265. https://doi.org/10.1080/19336896.2018.1525256
Walther T, Farese R (2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714. https://doi.org/10.1146/annurev-biochem-061009-102430.Lipid
Welte MA (2015) Expanding roles for lipid droplets. Curr Biol 25:470–481. https://doi.org/10.1016/j.cub.2015.04.004.Expanding
Wendell C, Zonderman A, Katzel L et al (2016) Nonlinear associations between plasma cholesterol levels and neuropsychological function. Neuropsychology 30:980–987. https://doi.org/10.1037/neu0000298.Nonlinear
West R, Beeri MS, Schmeidler J et al (2008) Better memory functioning associated with higher total and LDL cholesterol levels in very elderly subjects without the APOE4 allele. Am J Geriatr Psychiatry 16:781–785. https://doi.org/10.1097/JGP.0b013e3181812790.Better
Whitmer RA, Sidney S, Selby J et al (2005) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64:277–281. https://doi.org/10.1212/01.WNL.0000149519.47454.F2
WHO (2017) Global action plan on the public health response to dementia 2017 - 2025. WHO, Geneva. https://www.who.int/mental_health/neurology/dementia/action_plan_2017_2025/en/
WHO, ADI (2012) Dementia: a public health priority. https://www.who.int/mental_health/publications/dementia_report_2012/en/
Wollmer MA, Streffer JR, Tsolaki M et al (2003) Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer’s disease. Mol Psychiatry 8:635–638. https://doi.org/10.1038/sj.mp.4001296
Wolozin B (2000) Decreased prevalence of alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57:1439. https://doi.org/10.1001/archneur.57.10.1439
Wood GW, Ling L, Muller W, Eckert G (2014) Cholesterol as a causative agent in Alzheimer disease: a debatable hypothesis. J Neurochem 129:559–572. https://doi.org/10.1111/jnc.12637.Cholesterol
Xie C, Lund EG, Turley SD et al (2003) Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration. J Lipid Res 44:1780–1789. https://doi.org/10.1194/jlr.M300164-JLR200
Yamanaka K, Urano Y, Takabe W et al (2014) Induction of apoptosis and necroptosis by 24 (S)-hydroxycholesterol is dependent on activity of acyl-CoA: cholesterol acyltransferase 1. Cell Death Dis 5:990–999. https://doi.org/10.1038/cddis.2013.524
Yin YW, Li JC, Wang JZ et al (2012) Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a meta-analysis. Neurosci Lett 514:6–11. https://doi.org/10.1016/j.neulet.2012.02.031
Zhang J, Liu Q (2015) Cholesterol metabolism and homeostasis in the brain. Prot Cell 6:254–264. https://doi.org/10.1007/s13238-014-0131-3
Zhao FG, Wang YH, Yang JF et al (2005) Association between acyl-coenzyme A: Cholesterol acyltransferase gene and risk for Alzheimer’s disease in Chinese. Neurosci Lett 388:17–20. https://doi.org/10.1016/j.neulet.2005.06.020
Zhao B, Shang S, Li P et al (2019) The gender- and age-dependent relationships between serum lipids and cognitive impairment: a cross-sectional study in a rural area of Xi’an, China. Lipids Health Dis 18:1–11
Zlokovic BV, Deane R, Sagare AP et al (2010) Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain. J Neurochem 115:1077–1089. https://doi.org/10.1111/j.1471-4159.2010.07002.x.Low-density
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Alavez-Rubio, J.S., Juárez-Cedillo, T. (2022). Cholesterol and Dementia: A Possible Therapeutic Approach. In: Ashraf, G.M., Uddin, M.S. (eds) Current Thoughts on Dementia. Springer, Singapore. https://doi.org/10.1007/978-981-16-7606-2_13
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