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. 2013 Dec 19;30(1):162–168. doi: 10.1007/s12264-013-1391-2

Clusterin in Alzheimer’s disease: a player in the biological behavior of amyloid-beta

Xiang Li 1, Yifei Ma 1, Xu Wei 1, Yanpeng Li 1, Huijuan Wu 1, Jianhua Zhuang 1,✉, Zhongxin Zhao 1,✉
PMCID: PMC5562576  PMID: 24353014

Abstract

Alzheimer’s disease (AD) remains a major killer, and although its pathogenesis varies, one dominant feature is an increase in the expression, formation, and sedimentation of senile plaques of amyloid-beta (Aβ) peptides in the brain. The chaperone protein clusterin has, since its first discovery at the end of the 20th century, been labeled as a cytoprotector. However, epigenetic studies showing that clusterin is associated with the severity and risk of AD, especially in the hippocampus, triggered studies to clarify its role in the pathogenesis of AD. It is true that clusterin can inhibit the aggregation of Aβ and therefore prevent further formation of senile plaques in the AD brain, yet it induces the formation of soluble forms of Aβ which are toxic to neurons. Another problematic finding is that clusterin is involved in a pathway through which Aβ has neurodegenerative effects intracellularly. Although the role of clusterin in the pathogenesis of AD is still not clear, this review specifically discusses the interactions between clusterin and Aβ, to open up the possibility of a potential therapeutic approach for treating AD.

Keywords: clusterin, Alzheimer’s disease, amyloid-beta peptides, cytotoxicity, cytoprotection

Footnotes

These authors contributed equally to this work.

Contributor Information

Jianhua Zhuang, Email: jianhuazh11@126.com.

Zhongxin Zhao, Email: zhaozx@medmail.com.cn.

References

  • [1].Choi-Miura NH, Oda T. Relationship between multifunctional protein “clusterin” and Alzheimer disease. Neurobiol Aging. 1996;17:717–722. [PubMed] [Google Scholar]
  • [2].Calero M, Rostagno A, Frangione B, Ghiso J. Clusterin and Alzheimer’s disease. Subcell Biochem. 2005;38:273–298. doi: 10.1007/0-387-23226-5_14. [DOI] [PubMed] [Google Scholar]
  • [3].Calero M, Rostagno A, Matsubara E, Zlokovic B, Frangione B, Ghiso J. Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc Res Tech. 2000;50:305–315. doi: 10.1002/1097-0029(20000815)50:4<305::AID-JEMT10>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  • [4].Ling IF, Bhongsatiern J, Simpson JF, Fardo DW, Estus S. Genetics of clusterin isoform expression and Alzheimer’s disease risk. PLoS One. 2012;7:e33923. doi: 10.1371/journal.pone.0033923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer’s disease. Brain Res Rev. 2009;61:89–104. doi: 10.1016/j.brainresrev.2009.05.007. [DOI] [PubMed] [Google Scholar]
  • [6].Lambert JC, Amouyel P. Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Curr Opin Genet Dev. 2011;21:295–301. doi: 10.1016/j.gde.2011.02.002. [DOI] [PubMed] [Google Scholar]
  • [7].Yu JT, Tan L. The role of clusterin in Alzheimer’s disease: pathways, pathogenesis, and therapy. Mol Neurobiol. 2012;45:314–326. doi: 10.1007/s12035-012-8237-1. [DOI] [PubMed] [Google Scholar]
  • [8].Baig S, Palmer LE, Owen MJ, Williams J, Kehoe PG, Love S. Clusterin mRNA and protein in Alzheimer’s disease. J Alzheimers Dis. 2012;28:337–344. doi: 10.3233/JAD-2011-110473. [DOI] [PubMed] [Google Scholar]
  • [9].Xiao AW, He J, Wang Q, Luo Y, Sun Y, Zhou YP, et al. The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease. Neurosci Bull. 2011;27:287–299. doi: 10.1007/s12264-011-1736-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Giannakopoulos P, Kovari E, French LE, Viard I, Hof PR, Bouras C. Possible neuroprotective role of clusterin in Alzheimer’s disease: a quantitative immunocytochemical study. Acta Neuropathol. 1998;95:387–394. doi: 10.1007/s004010050815. [DOI] [PubMed] [Google Scholar]
  • [11].Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti GM, Morgan TE, et al. Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1–42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol. 1995;136:22–31. doi: 10.1006/exnr.1995.1080. [DOI] [PubMed] [Google Scholar]
  • [12].Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39:15953–15960. doi: 10.1021/bi002189x. [DOI] [PubMed] [Google Scholar]
  • [13].Yerbury JJ, Poon S, Meehan S, Thompson B, Kumita JR, Dobson CM, et al. The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures. FASEB J. 2007;21:2312–2322. doi: 10.1096/fj.06-7986com. [DOI] [PubMed] [Google Scholar]
  • [14].Guenette SY. Mechanisms of Abeta clearance and catabolism. Neuromolecular Med. 2003;4:147–160. doi: 10.1385/NMM:4:3:147. [DOI] [PubMed] [Google Scholar]
  • [15].Hammad SM, Ranganathan S, Loukinova E, Twal WO, Argraves WS. Interaction of apolipoprotein J-amyloid betapeptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. J Biol Chem. 1997;272:18644–18649. doi: 10.1074/jbc.272.30.18644. [DOI] [PubMed] [Google Scholar]
  • [16].Zlokovic BV, Martel CL, Matsubara E, McComb JG, Zheng G, McCluskey RT, et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci U S A. 1996;93:4229–4234. doi: 10.1073/pnas.93.9.4229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Hardy J, Guerreiro R, Lovestone S. Clusterin as an Alzheimer biomarker. Arch Neurol. 2011;68:1459–1460. doi: 10.1001/archneurol.2011.1000. [DOI] [PubMed] [Google Scholar]
  • [18].Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27:909–918. doi: 10.1038/sj.jcbfm.9600419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Pluta R. Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer’s disease brain. Curr Neurovasc Res. 2007;4:121–129. doi: 10.2174/156720207780637207. [DOI] [PubMed] [Google Scholar]
  • [20].Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998;95:6448–6453. doi: 10.1073/pnas.95.11.6448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].DeMattos RB, O’Dell M A, Parsadanian M, Taylor JW, Harmony JA, Bales KR, et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2002;99:10843–10848. doi: 10.1073/pnas.162228299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Llorca J, Rodriguez-Rodriguez E, Dierssen-Sotos T, Delgado-Rodriguez M, Berciano J, Combarros O. Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer’s disease. Acta Neurol Scand. 2008;117:1–14. doi: 10.1111/j.1600-0404.2007.00899.x. [DOI] [PubMed] [Google Scholar]
  • [23].Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, et al. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010;67:739–748. doi: 10.1001/archgenpsychiatry.2010.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Killick R, Ribe EM, Al-Shawi R, Malik B, Hooper C, Fernandes C, et al. Mol Psychiatry. 2012. Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Lin LF, Luo HM. Screening of treatment targets for Alzheimer’s disease from the molecular mechanisms of impairment by beta-amyloid aggregation and tau hyperphosphorylation. Neurosci Bull. 2011;27:53–60. doi: 10.1007/s12264-011-1040-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Narayan P, Orte A, Clarke RW, Bolognesi B, Hook S, Ganzinger KA, et al. The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-beta(1–40) peptide. Nat Struct Mol Biol. 2012;19:79–83. doi: 10.1038/nsmb.2191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Ghanim H, Monte SV, Sia CL, Abuaysheh S, Green K, Caruana JA, et al. Reduction in inflammation and the expression of amyloid precursor protein and other proteins related to Alzheimer’s disease following gastric bypass surgery. J Clin Endocrinol Metab. 2012;97:E1197–1201. doi: 10.1210/jc.2011-3284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Valproic acid stimulates clusterin expression in human astrocytes: Implications for Alzheimer’s disease. Neurosci Lett. 2010;475:64–68. doi: 10.1016/j.neulet.2010.03.041. [DOI] [PubMed] [Google Scholar]
  • [29].Conway KA, Baxter EW, Felsenstein KM, Reitz AB. Emerging beta-amyloid therapies for the treatment of Alzheimer’s disease. Curr Pharm Des. 2003;9:427–447. doi: 10.2174/1381612033391649. [DOI] [PubMed] [Google Scholar]
  • [30].Holtzman DM. In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. J Mol Neurosci. 2004;23:247–254. doi: 10.1385/JMN:23:3:247. [DOI] [PubMed] [Google Scholar]

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