Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Effect of High Cholesterol Regulation of LRP1 and RAGE on Aβ Transport Across the Blood-Brain Barrier in Alzheimer’s Disease

Author(s): Rui Zhou, Li-li Chen, Hai Yang, Ling Li, Juan Liu, Le Chen, Wen-Juan Hong, Cong-guo Wang, Jing-Jing Ma, Jie Huang, Xin-Fu Zhou, Dong Liu and Hua-Dong Zhou*

Volume 18 , Issue 5 , 2021

Published on: 06 September, 2021

Page: [428 - 442] Pages: 15

DOI: 10.2174/1567205018666210906092940

Price: $65


Background: High cholesterol aggravates the risk development of Alzheimer's disease (AD). AD is closely related to the transport impairment of Amyloid-β (Aβ) in the blood-brain barrier. It is unclear whether high cholesterol affects the risk of cognitive impairment in AD by affecting Aβ transport. The purpose of the study is to investigate whether high cholesterol regulates Aβ transport through low-density Lipoprotein Receptor-Related Protein 1 (LRP1) and Receptor for Advanced Glycation End products (RAGE) in the risk development of AD.

Methods: We established high cholesterol AD mice model. The learning and memory functions were evaluated by Morris Water Maze (MWM). Cerebral microvascular endothelial cells were isolated, cultured, and observed. The expression levels of LRP1 and RAGE of endothelial cells and their effect on Aβ transport in vivo were observed. The expression level of LRP1 and RAGE was detected in cultured microvessels after using Wnt inhibitor DKK-1 and β-catenin inhibitor XAV-939.

Results: Hypercholesterolemia exacerbated spatial learning and memory impairment. Hypercholesterolemia increased serum Aβ40 level, while serum Aβ42 level did not change significantly. Hypercholesterolemia decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells. Hypercholesterolemia increased brain apoptosis in AD mice. In in vitro experiment, high cholesterol decreased LRP1 expression and increased RAGE expression, increased Aβ40 expression in cerebral microvascular endothelial cells. High cholesterol regulated the expressions of LRP1 and RAGE and transcriptional activity of LRP1 and RAGE promoters by the Wnt/β-catenin signaling pathway.

Conclusion: High cholesterol decreased LRP1 expression and increased RAGE expression in cerebral microvascular endothelial cells, which led to Aβ transport disorder in the blood-brain barrier. Increased Aβ deposition in the brain aggravated apoptosis in the brain, resulting to cognitive impairment of AD mice.

Keywords: Alzheimer's disease, high cholesterol, low-density lipoprotein receptor-related protein, receptor for advanced glycation end products, amyloid-β, blood-brain barrier.

Jia L, Quan M, Fu Y, et al. Dementia in China: Epidemiology, clinical management, and research advances. Lancet Neurol 2020; 19(1): 81-92.
[] [PMID: 31494009]
Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2019; 394(10204): 1145-58.
[] [PMID: 31248666]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate alzheimer’s disease. N Engl J Med 2018; 378(18): 1691-703.
[] [PMID: 29719179]
Wang J, Jin WS, Bu XL, et al. Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies. Acta Neuropathol 2018; 136(4): 525-36.
[] [PMID: 30074071]
Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ. Immunotherapy for Alzheimer disease: The challenge of adverse effects. Nat Rev Neurol 2012; 8(8): 465-9.
[] [PMID: 22751529]
Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004; 62(6): 925-31.
[] [PMID: 15037694]
Jeong S. Molecular and cellular basis of neurodegeneration in alzheimer’s disease. Mol Cells 2017; 40(9): 613-20.
[PMID: 28927263]
Willén K, Edgar JR, Hasegawa T, Tanaka N, Futter CE, Gouras GK. Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A. Mol Neurodegener 2017; 12(1): 61.
[] [PMID: 28835279]
Donohue MC, Sperling RA, Petersen R, Sun CK, Weiner MW, Aisen PS. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA 2017; 317(22): 2305-16.
[] [PMID: 28609533]
Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 2010; 330(6012): 1774.
[] [PMID: 21148344]
O’Brien JT, Markus HS. Vascular risk factors and Alzheimer’s disease. BMC Med 2014; 12: 218.
[] [PMID: 25385509]
Zambón D, Quintana M, Mata P, et al. Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med 2010; 123(3): 267-74.
[] [PMID: 20193836]
Llorente-Cortes V, Casani L, Cal R, et al. Cholesterol-lowering strategies reduce vascular LRP1 overexpression induced by hypercholesterolaemia. Eur J Clin Invest 2011; 41(10): 1087-97.
[] [PMID: 21434892]
Yang H, Wang Y, Kar S. Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes. Glia 2017; 65(11): 1728-43.
[] [PMID: 28722194]
Chang TY, Yamauchi Y, Hasan MT, Chang C. Cellular cholesterol homeostasis and Alzheimer’s disease. J Lipid Res 2017; 58(12): 2239-54.
[] [PMID: 28298292]
Pedrini S, Thomas C, Brautigam H, et al. Dietary composition modulates brain mass and solubilizable Abeta levels in a mouse model of aggressive Alzheimer’s amyloid pathology. Mol Neurodegener 2009; 4: 40.
[] [PMID: 19845940]
Wang R, Li JJ, Diao S, et al. Metabolic stress modulates Alzheimer’s β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab 2013; 17(5): 685-94.
[] [PMID: 23663737]
Park HJ, Shabashvili D, Nekorchuk MD, et al. Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-β (Aβ) production by altering trafficking of γ-secretase and amyloid precursor protein (APP). J Biol Chem 2012; 287(48): 40629-40.
[] [PMID: 23043097]
Löffler T, Flunkert S, Temmel M, Hutter-Paier B. Decreased plasma Aβ in hyperlipidemic APPSL transgenic mice is associated with BBB dysfunction. Front Neurosci 2016; 10: 232.
[] [PMID: 27313503]
Do TM, Dodacki A, Alata W, et al. Age-dependent regulation of the blood-brain barrier influx/efflux equilibrium of amyloid-β peptide in a mouse model of Alzheimer’s disease (3xTg-AD). J Alzheimers Dis 2016; 49(2): 287-300.
[] [PMID: 26484906]
Kut C, Grossman SA, Blakeley J. How critical is the blood-brain barrier to the development of neurotherapeutics? JAMA Neurol 2015; 72(4): 381-2.
[] [PMID: 25642802]
Erickson MA, Hansen K, Banks WA. Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: Protection by the antioxidant N-acetylcysteine. Brain Behav Immun 2012; 26(7): 1085-94.
[] [PMID: 22809665]
Chen C, Li XH, Tu Y, et al. Aβ-AGE aggravates cognitive deficit in rats via RAGE pathway. Neuroscience 2014; 257: 1-10.
[] [PMID: 24188791]
Kim DE, Priefer R. Therapeutic potential of direct clearance of the amyloid-β in Alzheimer’s disease. Brain Sci 2020; 10(2)E93
[] [PMID: 32050618]
Jaya Prasanthi RP, Schommer E, Thomasson S, Thompson A, Feist G, Ghribi O. Regulation of beta-amyloid levels in the brain of cholesterol-fed rabbit, a model system for sporadic Alzheimer’s disease. Mech Ageing Dev 2008; 129(11): 649-55.
[] [PMID: 18845178]
Wang YJ, Zhou HD, Zhou XF. Clearance of amyloid-beta in Alzheimer’s disease: Progress, problems and perspectives. Drug Discov Today 2006; 11(19-20): 931-8.
[] [PMID: 16997144]
Bracko O, Vinarcsik LK, Cruz Hernández JC, et al. High fat diet worsens Alzheimer’s disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, but not by synergistically decreasing cerebral blood flow. Sci Rep 2020; 10(1): 9884.
[] [PMID: 32555372]
Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 2019; 22(3): 401-12.
[] [PMID: 30742114]
Shin EJ, Park JH, Sung MJ, Chung MY, Hwang JT. Citrus junos Tanaka peel ameliorates hepatic lipid accumulation in HepG2 cells and in mice fed a high-cholesterol diet. BMC Complement Altern Med 2016; 16(1): 499.
[] [PMID: 27912736]
Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106(12): 1489-99.
[] [PMID: 11120756]
Cui H, Zhu Y, Jiang D. The RIP1-RIP3 complex mediates osteocyte necroptosis after ovariectomy in rats. PLoS One 2016; 11(3)e0150805
[] [PMID: 26985994]
Morales-Corraliza J, Schmidt SD, Mazzella MJ, et al. Immunization targeting a minor plaque constituent clears β-amyloid and rescues behavioral deficits in an Alzheimer’s disease mouse model. Neurobiol Aging 2013; 34(1): 137-45.
[] [PMID: 22608241]
Taylor SC, Posch A. The design of a quantitative western blot experiment. BioMed Res Int 2014; 2014361590
[] [PMID: 24738055]
Xue-Shan Z, Juan P, Qi W, et al. Imbalanced cholesterol metabolism in Alzheimer’s disease. Clin Chim Acta 2016; 456: 107-14.
[] [PMID: 26944571]
Solomon A, Kåreholt I, Ngandu T, et al. Serum cholesterol changes after midlife and late-life cognition: Twenty-one-year follow-up study. Neurology 2007; 68(10): 751-6.
[] [PMID: 17339582]
Helzner EP, Luchsinger JA, Scarmeas N, et al. Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 2009; 66(3): 343-8.
[] [PMID: 19273753]
Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol 2011; 68(10): 1239-44.
[] [PMID: 21987540]
Longenberger J, Shah ZA. Simvastatin and other HMG-CoA reductase inhibitors on brain cholesterol levels in Alzheimer’s disease. Curr Alzheimer Res 2011; 8(4): 434-42.
[] [PMID: 21244355]
Lin FC, Chuang YS, Hsieh HM, et al. Early statin use and the progression of alzheimer disease: A total population-based case-control study. Medicine (Baltimore) 2015; 94(47)e2143
[] [PMID: 26632742]
Ismail N, Ismail M, Azmi NH, et al. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomed Pharmacother 2017; 95: 780-8.
[] [PMID: 28892789]
Cai Z, Qiao PF, Wan CQ, Cai M, Zhou NK, Li Q. Role of blood-brain barrier in Alzheimer’s disease. J Alzheimers Dis 2018; 63(4): 1223-34.
[] [PMID: 29782323]
Yin K, Jin J, Zhu X, et al. CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice. Neurol Res 2017; 39(10): 885-94.
[] [PMID: 28743230]
Ashok A, Rai NK, Raza W, Pandey R, Bandyopadhyay S. Chronic cerebral hypoperfusion-induced impairment of Aβ clearance requires HB-EGF-dependent sequential activation of HIF1α and MMP9. Neurobiol Dis 2016; 95: 179-93.
[] [PMID: 27431094]
Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 2006; 112(4): 405-15.
[] [PMID: 16865397]
Ma LY, Fei YL, Wang XY, et al. The Research on the Relationship of RAGE, LRP-1, and Aβ Accumulation in the Hippocampus, Prefrontal Lobe, and Amygdala of STZ-Induced Diabetic Rats. J Mol Neurosci 2017; 62(1): 1-10.
[] [PMID: 28401370]
Moir RD, Tanzi RE. LRP-mediated clearance of Abeta is inhibited by KPI-containing isoforms of APP. Curr Alzheimer Res 2005; 2(2): 269-73.
[] [PMID: 15974929]
Sharma HS, Castellani RJ, Smith MA, Sharma A. The blood-brain barrier in Alzheimer’s disease: Novel therapeutic targets and nanodrug delivery. Int Rev Neurobiol 2012; 102: 47-90.
[] [PMID: 22748826]
Liu CC, Hu J, Zhao N, et al. Astrocytic lrp1 mediates brain aβ clearance and impacts amyloid deposition. J Neurosci 2017; 37(15): 4023-31.
[] [PMID: 28275161]
Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: Evidence from clinical and preclinical studies. J Lipid Res 2017; 58(7): 1267-81.
[] [PMID: 28381441]
Storck SE, Meister S, Nahrath J, et al. Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier. J Clin Invest 2016; 126(1): 123-36.
[] [PMID: 26619118]
Van Gool B, Storck SE, Reekmans SM, et al. LRP1 has a predominant role in production over clearance of aβ in a mouse model of alzheimer’s disease. Mol Neurobiol 2019; 56(10): 7234-45.
[] [PMID: 31004319]
Rauch JN, Luna G, Guzman E, et al. LRP1 is a master regulator of tau uptake and spread. Nature 2020; 580(7803): 381-5.
[] [PMID: 32296178]
Candela P, Gosselet F, Saint-Pol J, et al. Apical-to-basolateral transport of amyloid-β peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. J Alzheimers Dis 2010; 22(3): 849-59.
[] [PMID: 20858979]
Cui L, Cai Y, Cheng W, et al. A novel, multi-target natural drug candidate, matrine, improves cognitive deficits in alzheimer’s disease transgenic mice by inhibiting aβ aggregation and blocking the rage/aβ axis. Mol Neurobiol 2017; 54(3): 1939-52.
[] [PMID: 26899576]
Derk J, MacLean M, Juranek J, Schmidt AM. The receptor for advanced glycation endproducts (rage) and mediation of inflammatory neurodegeneration. J Alzheimers Dis Parkinsonism 2018; 8(1): 421.
[] [PMID: 30560011]
Ding B, Lin C, Liu Q, et al. Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. J Neuroinflammation 2020; 17(1): 302.
[] [PMID: 33054814]
Fani Maleki A, Cisbani G, Plante MM, et al. Muramyl dipeptide-mediated immunomodulation on monocyte subsets exerts therapeutic effects in a mouse model of Alzheimer’s disease. J Neuroinflammation 2020; 17(1): 218.
[] [PMID: 32698829]
Wang H, Chen F, Du YF, et al. Targeted inhibition of RAGE reduces amyloid-β influx across the blood-brain barrier and improves cognitive deficits in db/db mice. Neuropharmacology 2018; 131: 143-53.
[] [PMID: 29248482]
Fang F, Yu Q, Arancio O, et al. RAGE mediates Aβ accumulation in a mouse model of Alzheimer’s disease via modulation of β- and γ-secretase activity. Hum Mol Genet 2018; 27(6): 1002-14.
[] [PMID: 29329433]
Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996; 382(6593): 685-91.
[] [PMID: 8751438]
C RC. Lukose B, Rani P. G82S RAGE polymorphism influences amyloid-RAGE interactions relevant in Alzheimer’s disease pathology. PLoS One 2020; 15(10)e0225487
[] [PMID: 33119615]
Zhang H, Wang Y, Yan S, et al. Genetic deficiency of neuronal RAGE protects against AGE-induced synaptic injury. Cell Death Dis 2014; 5(6)e1288
[] [PMID: 24922072]
Wang P, Huang R, Lu S, et al. RAGE and AGEs in mild cognitive impairment of diabetic patients: A cross-sectional study. PLoS One 2016; 11(1)e0145521
[] [PMID: 26745632]
Kuntz M, Candela P, Saint-Pol J, et al. Bexarotene promotes cholesterol efflux and restricts apical-to-basolateral transport of amyloid-β peptides in an in vitro model of the human blood-brain barrier. J Alzheimers Dis 2015; 48(3): 849-62.
[] [PMID: 26402114]
Wahrle SE, Jiang H, Parsadanian M, et al. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 2005; 280(52): 43236-42.
[] [PMID: 16207708]
Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell 2015; 6(4): 254-64.
[] [PMID: 25682154]
Jiang X, Guo M, Su J, et al. Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. Int J Alzheimers Dis 2012; 2012109324
[] [PMID: 22506129]
Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: Potential novel targets for treatment. J Steroid Biochem Mol Biol 2019; 190: 104-14.
[] [PMID: 30878503]
Chang KW, Zong HF, Ma KG, et al. Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways. Neurochem Int 2018; 120: 238-50.
[] [PMID: 30217465]
Yang TT, Hsu CT, Kuo YM. Cell-derived soluble oligomers of human amyloid-beta peptides disturb cellular homeostasis and induce apoptosis in primary hippocampal neurons. J Neural Transm (Vienna) 2009; 116(12): 1561-9.
[] [PMID: 19809865]
Long Z, Zheng M, Zhao L, et al. Valproic acid attenuates neuronal loss in the brain of APP/PS1 double transgenic Alzheimer’s disease mice model. Curr Alzheimer Res 2013; 10(3): 261-9.
[] [PMID: 23036022]
LaFerla FM, Hall CK, Ngo L, Jay G. Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice. J Clin Invest 1996; 98(7): 1626-32.
[] [PMID: 8833912]
Zhou L, Chen D, Huang XM, et al. Wnt5a promotes cortical neuron survival by inhibiting cell-cycle activation. Front Cell Neurosci 2017; 11: 281.
[] [PMID: 29033786]
Borrell-Pagès M, Romero JC, Badimon L. LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice. J Cell Mol Med 2015; 19(4): 770-7.
[] [PMID: 25656427]
Liu L, Wan W, Xia S, Kalionis B, Li Y. Dysfunctional Wnt/β-catenin signaling contributes to blood-brain barrier breakdown in Alzheimer’s disease. Neurochem Int 2014; 75: 19-25.
[] [PMID: 24859746]
Vallon M, Yuki K, Nguyen TD, et al. A RECK-WNT7 receptor-ligand interaction enables isoform-specific regulation of wnt bioavailability. Cell Rep 2018; 25(2): 339-349.e9.
[] [PMID: 30304675]
Patel MM, Behar AR, Silasi R, et al. Role of ADTRP (androgen-dependent tissue factor pathway inhibitor regulating protein) in vascular development and function. J Am Heart Assoc 2018; 7(22)e010690
[] [PMID: 30571485]
Li HF, Liu JY. Effects of MiR-26a on respiratory distress syndrome in neonatal rats via the wnt/β-catenin signaling pathway. Eur Rev Med Pharmacol Sci 2019; 23(6): 2525-31.
[PMID: 30964179]
Azizian-Farsani F, Abedpoor N, Hasan Sheikhha M, Gure AO, Nasr-Esfahani MH, Ghaedi K. Receptor for advanced glycation end products acts as a fuel to colorectal cancer development. Front Oncol 2020; 10552283
[] [PMID: 33117687]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy