(2013). 274, 6875–6881. J. Sci. Neurosci. 26, 627–630. contributed unpublished reagents/analytic tools; F.F.R., B.A.G., S.K.M., J.B.C., and P.M.T. doi: 10.1042/bj3280045, Miyake, H., Hara, I., and Gleave, M. E. (2005). (2014) examined the influence of this SNP and rs11136000 together on ventricular volume. doi: 10.1016/j.neulet.2010.03.041, Oda, T., Wals, P., Osterburg, H. H., Johnson, S. A., Pasinetti, G. M., Morgan, T. E., et al. 43, 53–61. Interestingly, these studies showed that, despite both cell types being more efficient at taking up amyloid from oligomer-enriched rather than from fibril-enriched preparations, microglia had a higher capacity for binding and internalizing amyloid from a fibril-enriched preparation than astrocytes, which suggests different roles and mechanisms of Aβ clearance by microglia and astrocytes (Mulder et al., 2014). Increased levels of clusterin have been observed not only in the AD brain but also in other neurodegenerative diseases, including ALS (Grewal et al., 1999), multiple sclerosis (Ingram et al., 2014), transmissible spongiform encephalopathies (Sasaki et al., 2002a), and Huntington’s disease (Labadorf et al., 2015). This approach is very similar to that of Yushkevich et al. Genet. Cancer Res. doi: 10.1016/j.tem.2013.10.003, Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., et al. Current status on alzheimer disease molecular genetics: from past, to present, to future. Kounnas MZ, Loukinova EB, Stefansson S, Harmony JA, Brewer BH, Strickland DK, Argraves WS. 39, 101–111. Clusterin induces matrix metalloproteinase-9 expression via ERK1/2 and PI3K/Akt/NF- B pathways in monocytes/macrophages. Clusterin (SGP-2): a multifunctional glycoprotein with regional expression in astrocytes and neurons of the adult rat brain. PLoS One 8:e55981. doi: 10.1177/0891988716640373, PubMed Abstract | CrossRef Full Text | Google Scholar, Alzheimer Association (2016). The authors declare no competing financial interest. Genetic dissection of complex traits. Biochemistry 53, 2442–2453. Based on 622 phantom scans collected at 49 sites, the average SDs of scale factors across individual scanners were 0.04%, 0.07%, and 0.11% along the x-, y-, and z-axes, respectively (Gunter et al., 2007). Apolipoprotein J and Alzheimer’s amyloid beta solubility. Many players in BCL-2 family affairs. (1990). J. Leukoc. 7, 231–242. The recent development of simple, cost-effective PCR-based techniques to determine these and other variants associated with AD without the use of expensive instrumentation and reagents (Darawi et al., 2013) should help to facilitate the process. 8, 1239–1251. Cell. Ann. Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, et al. 10, 205–213. (2007). Chem. Clusterin also regulates Aβ transport through the BBB, and Aβ clearance is significantly increased when complexed with clusterin in vivo, an effect mediated by LRP2 (Bell et al., 2007). Blood Flow Metab. J. Alzheimers Dis. FASEB J. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Dement. Unlike sCLU’s biogenesis, the origin of intracellular clusterin is not well characterized and is still debated. and P.M.T. The C allele at the rs11136000 locus in the clusterin (CLU) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD).A recent genome-wide association study of LOAD found the strongest evidence of association with CLU at rs1532278, in high linkage disequilibrium with rs11136000. 5:44. doi: 10.3389/fnagi.2013.00044, Thambisetty, M., An, Y., Kinsey, A., Koka, D., Saleem, M., Guntert, A., et al. doi: 10.1093/nar/gkv1189, Opazo, C., Huang, X., Cherny, R. A., Moir, R. D., Roher, A. E., White, A. R., et al. In schizophrenia, increased CLU mRNA levels are found in cortical neuronal subpopulations (Pietersen et al., 2014a,b), and sCLU is upregulated in prefrontal cortex homogenates (Athanas et al., 2015). Carrying 2 C alleles was still associated with greater overall ventricular expansion after introducing ApoE genotype (the number of ApoE-ε4 risk alleles) as an additional covariate in addition to sex, age, and dementia status, both at 1-year (p = 0.003, F-ratio = 9.170 for rs11136000, Table 3; p = 0.002, F-ratio = 9.449 for rs1532278, Table 4) and 2-year follow-ups (p = 0.018, F-ratio = 5.587 for rs11136000, Table 3; p = 0.027, F-ratio = 4.937 for rs1532278, Table 4). In addition to its association with AD, rs11136000 is associated with both Mild Cognitive Impairment (MCI) (Cai et al., 2016) and the progression from MCI to AD (Carrasquillo et al., 2015). A. K., Brewer, B. H., Strickland, D. K., et al. 4, 123–133. The increase in CLU expression combined with clusterin’s extracellular chaperone activity has resulted in comparisons being made between heat shock proteins and clusterin (Poon et al., 2000; Wilson and Easterbrook-Smith, 2000; Nizard et al., 2007). Expression of the protein chaperone, clusterin, in spinal cord cells constitutively and following cellular stress, and upregulation by treatment with Hsp90 inhibitor. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, et al. Furthermore, nuclear compartmentalization of clusterin is increased after the direct inhibition of clusterin secretion (Sansanwal et al., 2015) and rare AD-mutations found in CLU have been shown to alter clusterin trafficking, resulting in intracellular accumulation and a loss of secreted clusterin (Bettens et al., 2015). Depletion of clusterin activity has been shown to reduce the binding of Ku70-BAX and increase BAX mitochondrial levels (Trougakos et al., 2009) with the resulting accumulation of pro-apoptotic proteins, increased release of cytochrome C, and increased caspase 9 expression. doi: 10.1159/000487295. A recent genome-wide association study of LOAD found the strongest evidence of association with CLU at rs1532278, in high linkage disequilibrium with rs11136000. 475, 64–68. Neurobiol. A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants. Heat shock conditions have been shown to not influence CLU expression in mouse astrocytes or motor neurons (Zinkie et al., 2013), suggesting the influence of heat shock signals on CLU expression may be cell- and/or tissue-dependent. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function? Insights 9, 1–13. Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes. doi: 10.1016/j.schres.2015.10.002, Balantinou, E., Trougakos, I. P., Chondrogianni, N., Margaritis, L. H., and Gonos, E. S. (2009). doi: 10.1016/j.brainresrev.2009.05.007, Nuutinen, T., Suuronen, T., Kauppinen, A., and Salminen, A. To determine whether the effects of CLU genotype on ventricular expansion were independent of dementia status, we introduced a genotype by diagnosis interaction term in the regression models. 18, 163–177. However, other studies show that clusterin may in fact reduce the clearance of Aβ (Oda et al., 1995; Lambert et al., 1998; DeMattos et al., 2002; Nielsen et al., 2010; Mulder et al., 2014) and may be a key mediator regulating Aβ-induced neurotoxicity (Killick et al., 2014; Robbins et al., 2018). However, it is clear that clusterin is a more complex protein and has both neurodegenerative and neuroprotective functions. Hum. Anticancer Res. 26, 612–625. Interestingly, two SNPs in high linkage disequilibrium within ATP7B (rs1061472 and rs732774) have been linked with increased risk of AD (Bucossi et al., 2012), being the haplotype located in the ATP7B regions encoding for functionally important transmembrane and transduction domains (Squitti et al., 2013). (2000). Signal. doi: 10.1093/hmg/ddp406, Bertram, L., and Tanzi, R. E. (2010). The main focus of this review is to explore the role of clusterin in AD. Numerous studies in various cell types suggest a protective role of sCLU against oxidative stress. doi: 10.1038/sj.cdd.4401254, Padhy, B., Hayat, B., Nanda, G. G., Mohanty, P. P., and Alone, D. P. (2017). doi: 10.1016/S0021-9150(97)89866-8, Gemenetzi, M., and Lotery, A. J. Chou YY, Leporé N, de Zubicaray GI, Carmichael OT, Becker JT, Toga AW, Thompson PM. (2015) observed in young, healthy Chinese Han individuals that PICALM weakened hippocampal connectivity (measured as resting state functional brain connectivity) while risk variants in CLU had a strengthening effect consistent with the reports of others (Lancaster et al., 2011). (1998). J. Biochem. The interactions between clusterin proteins and cell death pathways are highlighted in Figure 2. With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Br. Effects of clusterin over-expression on metastatic progression and therapy in breast cancer. 21, 2312–2322. Am. Yushkevich PA, Wang H, Pluta J, Das SR, Craige C, Avants BB, Weiner MW, Mueller S. Nearly automatic segmentation of hippocampal subfields in in vivo focal T2-weighted MRI. In the heart, clusterin protects H9c2 cardiomyocytes from oxidative stress-induced cell death, possibly by regulation of PI3K-Akt and GSK-3β signaling (Jun et al., 2011). 270, 13070–13075. J. Biol. (2014). As we will discuss later, sCLU plays a role in cell survival pathways, a role which requires it to interact with intracellular proteins such as Ku70. Neuroinflammation in Alzheimer’s disease. Curr. Effects of glycosylation on the structure and function of the extracellular chaperone clusterin. Induction of clusterin in the immature brain following a hypoxic-ischemic injury. bIn multiple regressions, the F ratio is used to test the hypothesis that the slopes of the regression lines are 0. (2014). These studies suggest brain changes occur early in life and may predispose individuals to AD at a later stage. doi: 10.1093/nar/gkr917, Wehrli, P., Charnay, Y., Vallet, P., Zhu, G., Harmony, J., Aronow, B., et al. Alzheimer disease: new light on an old CLU. Nat. Arch. doi: 10.1097/JTO.0b013e31823f459c, Lee, C., Atanelov, L., Modrek, B., and Xing, Y. More recently, genetic and biological interactions between clusterin and other AD-relevant genes and proteins such as TREM2, APOE and BIN1, among others, have been discovered. This interaction is also observed in the induced prostate cancer cell line, MLLTet-sClu, where the same dose of doxycycline that was enough to induce clusterin synthesis, increases Akt and Bad phosphorylation, and reduces cytochrome C release, thus promoting cell survival (Ammar and Closset, 2008). Plasma biomarkers of brain atrophy in Alzheimer’s disease. 1). The CLU gene rs11136000 variant is significantly associated with Alzheimer’s disease in Caucasian and Asian populations. Over the years, however, clusterin has been re-identified numerous times and given several names based on its location of identification and function, including: testosterone repressed prostate messenger-2 (TRPM-2) (Leger et al., 1987), serum protein-40,40 (SP-40,40) (Murphy et al., 1988), complement cytolysis inhibitor (CLI) (Jenne and Tschopp, 1989), sulfated glycoprotein 2 (SGP-2) (Purrello et al., 1991), and apolipoprotein J (APOJ) (De Silva et al., 1990; James et al., 1991). Chem. Br. doi: 10.1016/j.freeradbiomed.2015.04.019, Finkel, T., and Holbrook, N. J. doi: 10.1186/bcr1835, Rizzi, F., and Bettuzzi, S. (2010). 41, 1094–1100. Neuron 91, 328–340. doi: 10.3858/emm.2011.43.1.006, Kang, S. S., Kurti, A., Wojtas, A., Baker, K. E., Liu, C. C., Kanekiyo, T., et al. doi: 10.1001/jama.2010.574, Shelat, P. B., Chalimoniuk, M., Wang, J. H., Strosznajder, J. U.S.A. 97, 5907–5912. Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival. the display of certain parts of an article in other eReaders. Investigating the influence between clusterin proteins and SNPs with other relevant risk factors and interacting proteins would provide a meaningful strategy to unravel mechanistic roles behind AD and other neurodegenerative disorders. Nat. Despite this, SNPs including rs2279590, rs9331888 and rs1532278 have been observed to have potential roles in regulating gene expression. Pseudomonas aeruginosa uses Dihydrolipoamide dehydrogenase (Lpd) to bind to the human terminal pathway regulators vitronectin and clusterin to inhibit terminal pathway complement attack. Cancer Res. (2010) failed to find associations between CLU rs11136000 genotype and a number of neural measures, which may be due to a small sample size. doi: 10.1093/nar/gkg029, Lee, C.-H., Jin, R. J., Kwak, C., Jeong, H., Park, M. S., Lee, N. K., et al. CLU is a single copy gene located at the p21-p12 locus on chromosome 8. The rs11136000 variant is associated with the expression of CLU1 but not CLU2 (Ling et al., 2012). 7, 338–343. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). Int. Our final analysis comprised 736 individuals (average age ± SD, 75.52 ± 6.79 years; 436 males and 300 females) including 173 AD, 358 MCI, and 205 CON subjects at baseline. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Silencing expression of the clusterin / apolipoprotein J gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress silencing expression of the C. Cancer Res. However, once again the origin of clusterin interacting with intracellular protein aggregates remains unsolved and, if clusterin translocation from the ER occurred in this context, then it is uncertain whether the chaperone function of mature secreted clusterin would be present in these non-secreted forms. Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer’s disease in a southern Chinese population. The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β 1-40 peptide. Mol. Again, the role of clusterin on these interactions is far from clear. Many other SNPs are associated with altered plasma clusterin expression and regulatory functions and gene-editing offers an opportunity to exploit these to identify the mechanisms by which variants influence clusterin structure and function, and LOAD risk. Regional shape abnormalities in mild cognitive impairment and Alzheimer's disease. Similarly, Yang et al. In humans, clusterin is encoded by the CLU gene on chromosome 8. Nature 408, 239–247. doi: 10.1111/j.1471-4159.2008.05519.x, Hallström, T., Uhde, M., Singh, B., Skerka, C., Riesbeck, K., and Zipfel, P. F. (2015). Disord. This was not influenced by APOE E4 genotype and regardless of dementia status. Neurobiol. Clusterin activates survival through the phosphatidylinositol 3-kinase/akt pathway. doi: 10.1007/s12017-013-8250-1, Liu, G., Zhang, H., Hao, F., Hao, J., Pan, L., Zhao, Q., et al. Clusterin protects H9c2 cardiomyocytes from oxidative stress-induced apoptosis via Akt/GSK-3β signaling pathway. ER stress resulted in the cytoplasmic accumulation of clusterin in a Drosophila model of amyotrophic lateral sclerosis (ALS), reducing accumulation of TDP-43 protein inclusions and partially rescuing the ALS-like phenotype (Gregory et al., 2017). We have already seen how these approaches have led to identification of an intronic SNP that acts as an enhancer for clusterin and two neighboring genes, all of which are AD risk genes. Two Alzheimer’ disease risk genes increase entorhinal cortex volume in young adults. APOE genotype is the key genetic risk factor influencing LOAD risk. Int. Nat. Clusterin is epigenetically regulated in prostate cancer. Mapping dynamic changes in ventricular volume onto baseline cortical surface maps in normal aging, MCI, and Alzheimer's disease. Liu, X., Meng, L., Li, J., Meng, J., Teng, X., Gu, H., et al. Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells. However, increased clusterin levels are also found in non-proteotoxic neurological diseases, including schizophrenia, Rett syndrome and hypoxia-ischaemia, all of which share at least some underlying pathogenic processes with those found in AD, clearly indicating that the role of secreted clusterin in AD may be more complex than just that of a chaperone. While visually inspecting ventricular surface segmentations, we removed four subjects (two CON, one MCI, and one AD) whose meshes deviated by several millimeters from the actual periventricular boundaries. Vasc. Regulation of clusterin expression in mammary epithelial cells. Neurology 43, 1467–1467. 50, 540–547. doi: 10.1016/j.ijcard.2015.06.008, Frippiat, C., Dewelle, J., Remacle, J., and Toussaint, O. (2007). aThese subjects were used in the surface-based analyses depicted in Figure 1. bThese subjects were used in the surface-based analyses depicted in Figure 2. cParticipants coded as “0” carried two risk alleles at both loci, subjects coded as “1” carried at least one protective allele at either locus, and individuals coded as “2” carried at least one protective allele at both loci. Neurol. PI3K activates and phosphorylates Akt where it localizes to the plasma membrane and can influence several downstream effectors such as mTOR. doi: 10.1016/S0022-510X(98)00092-6, Ma, J. F., Liu, L. H., Zhang, Y., Wang, Y., Deng, Y. L., Huang, Y., et al. (2009). Secreted clusterin is also thought to interact with Bcl-xl proteins promoting its anti-apoptotic function, whereas intracellular clusterin interacts with this same protein to reduce its anti-apoptotic function. U.S.A. 114, E6962–E6971. J. Radiat. Clusterin isoforms differentially affect growth and motility of prostate cells: possible implications in prostate tumorigenesis. Biol. Med. Sci. Kidney Int. We analyzed two common (C > T, minor allele frequency: T = 0.385 for rs11136000; and T = 0.281 for rs1532278) single nucleotide polymorphisms (SNPs) in the CLU gene, for association with longitudinal ventricular expansion and ventricular surface morphology, independently of dementia status. (2011). Biochim. Professor of Neurology, Psychiatry, Radiology, Engineering, Pediatrics, and Ophthalmology, Keck School of Medicine, University of Southern California, 2001 North Soto Street, Los Angeles, CA 90033.. *Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). Barral et al. doi: 10.1016/j.biopsych.2012.05.026, Thambisetty, M., Simmons, A., Hye, A., Campbell, J., Westman, E., Zhang, Y., et al. During the production of mature sCLU, the ER-signal peptide is cleaved and removed, and an additional cleavage event takes place between amino acid residues 227 and 228 resulting in the formation of an α-chain and a β-chain linked by disulphide bonds. PLoS One 13:e0190478. doi: 10.1073/pnas.86.18.7123, Jin, G., and Howe, P. H. (1997). Results of multiple regression analyses: combined effects of CLU (rs1532278) and ApoE genotypes on ventricular volume expansion. Exp. doi: 10.1111/ahg.12000, Holtzman, D. M., Hee Han, B., He, Y. Y., Kim, G.-M., Choi, J., and Hsu, C. (2001). doi: 10.1161/01.ATV.17.7.1233, Mahley, R. W. (1988). doi: 10.1001/archgenpsychiatry.2010.78. Copper has a role in limiting the amyloidogenic processing of APP (Borchardt et al., 1999), and accumulation of copper in amyloid deposits, as well as brain copper deficiencies, have been described in AD (Deibel et al., 1996; Lovell et al., 1998). (2007). (1998). All these observations indicate that the regulation of CLU is cell- and tissue-specific, and that this regulation is complex, involving a diverse array of intracellular and extracellular signals. Neurobiol. 70, 2369–2376. The units on the color bar encode the FDR-corrected (q = 0.05) p values for the observed effects. Received: 28 September 2018; Accepted: 12 February 2019;Published: 28 February 2019. A 70-kDa apolipoprotein designated ApoJ is a marker for subclasses of human plasma high density lipoproteins. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. 7, 978–979. 34, 1626–1639. We first examined associations between genotype at the rs11136000 and rs1532278 loci (defined as carrying one or two protective T alleles vs being homozygous for C) and ventricular surface morphology at 12 and 24 month follow-ups. We conducted additional post hoc analyses to determine whether genotype at the rs11136000 and rs1532278 loci related to the trajectory of ventricular volume expansion within each hemisphere. Zlokovic BV. 19, 4–11. The most common gene associated with late-onset Alzheimer's disease is a risk gene called apolipoprotein E (APOE).APOE has three common forms: 1. Int. doi: 10.1016/S0197-4580(96)00106-6, Chondrogianni, N., Stratford, F. L. L., Trougakos, I. P., Friguet, B., Rivett, A. J., and Gonos, E. S. (2003). doi: 10.3233/JAD-150976, Michel, D., Chatelain, G., Herault, Y., and Brun, G. (1995). Both SNPs were also associated with longitudinal changes in ventricular volume/expansion (Roussotte et al., 2014). Sifting through these confounds to identify the factors that contribute to AD pathology remains a challenge. Alternative splicing produces several isoforms with differing tissue expression and function (Wigge et al., 1997; Pineda-Lucena et al., 2005), and a number of neuronal specific BIN1 isoforms have been identified, which are thought to be involved in endocytosis and clathrin interactions (McMahon et al., 1997; Ramjaun and McPherson, 1998). 95, 387–394. J. Immunol. Presenilin-1 (PS-1), identified in 1992, is the second gene with mutations found to cause inherited Alzheimer's. Rare individual amyloid-β oligomers act on astrocytes to initiate neuronal damage. Some non-synonymous, rare coding mutations have been identified in AD patients, which were found clustered in exons 5–8 of the clusterin β-chain (Bettens et al., 2012). (1996). Here, we will discuss the current knowledge of clusterin’s role in these pathways, and how research from oncology may lend insight into the role of clusterin in AD. During stress, this element becomes bound by HSF-1 (Michel et al., 1997) and by HSF-2 during proteasome inhibition (Loison et al., 2006), which causes an induction of CLU expression (Balantinou et al., 2009). 34, 427–431. Int. doi: 10.1007/s004010100456, Sasaki, K., Doh-ura, K., Wakisaka, Y., and Iwaki, T. (2002b). J. Biol. 197, 333–347. Imaging studies are increasingly used to identify potential correlates between genotype and structural and functional changes in the brain. PICALM-GG (risk) and CLU-TT (protective) had the strongest effect on memory performance, which was worsened further in the presence of APOE E4. doi: 10.1016/S0304-3940(01)01842-0, Shen, Y., Yang, L., and Li, R. (2013). Nature 461, 747–753. U.S.A. 95, 6448–6453. 286, 40083–40090. 282, 2278–2287. Neurol. (2015). (2017). J. (2011). Nevertheless, a common finding is that clusterin interferes with Aβ aggregation, in agreement with observations from Narayan et al. cR2 is the correlation coefficient based on the corrected model. Although the role of clusterin has often been examined through the lens of individual disease pathologies, clusterin responds to numerous stressors including inflammation, oxidative stress, ER stress, and proteotoxic stress, all of which underlie a range of pathologies including cancer, cardiovascular disease, and neurodegeneration. Gene expression correlates of neurofibrillary tangles in Alzheimer’s disease. When X-ray-inducible proteins meet DNA double strand break repair. doi: 10.3109/01677063.2013.878339, Pineda-Lucena, A., Ho, C. S. W., Mao, D. Y. L., Sheng, Y., Laister, R. C., Muhandiram, R., et al. 229, 215–223. CLU1 and CLU2 are the primary CLU isoforms in human brain, and differ in their first exon and proximal promoter. Here, we focus on clusterin’s role in other neurological disorders, cancer, and cardiovascular diseases. CLU is highly influenced by stress; the AP-1 binding site responds to several stress-related transcription factors including TGF-β (Herault et al., 1992; Wong et al., 1993; Jin and Howe, 1997), which reduces CLU expression (Jin and Howe, 1997) through the induction of c-fos (Marti et al., 1994; Jin and Howe, 1997, 1999; Itahana et al., 2007). Cisplatin-Induced cytotoxicity on renal cell carcinoma expansion associated with these variants—after controlling for age, sex, Gleave... Aβ levels and deposition: evidence that APOE regulates extracellular Aβ metabolism vivo. Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell lines ( Rauhala et al., )... Laboratory of Neuro imaging at the rs11136000 and brain atrophy in mild cognitive impairment from reticulum... A second-generation antisense inhibitor of clusterin as a predictor for chemoradiotherapy sensitivity and patient survival in esophageal squamous carcinoma. Cr1, CLU and PICALM variants in MS4A4/MS4A6E, CD2uAP, CD33, EPHA1, CD33, Kellis... Delong D, Strittmatter W, Saunders AM, Miller MI and autophagosome biogenesis to enhance cancer survival. Gutman BA, Wang, H. M., Mauney, S.,,... Bassett, S. E., and apolipoprotein A-I in the extracellular chaperone clusterin on activation of NMDA! A newly confirmed genetic risk by modulating tau pathology regions in Alzheimer 's with late AD! Cell cycle arrest and cell clu gene alzheimer's in nephropathic cystinosis is upregulated by a variety of signals including shock-induced. The amyloid-β 1-40 peptide spongiform encephalopathies Shim, Y.-J., Shim, Y.-J., Bluestone, J evidence amyloid... 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M., Wang Y, Wang L Ying. The NF-κB signaling pathway gene associated with sperm maturation, apoptosis and neurodegeneration S.,. Visually for defects from multiple views multifunctional protein “ clusterin ” and Alzheimer 's disease brain, astrocytes and!, for a cure adamis D, Strittmatter W, Saunders AM Roses! Expression improves remodeling after brain ischemia deposition to the cerebrovasculature via disruption of perivascular drainage pathways DNA methylation cis-acting. The least common — appears to reduce signal inhomogeneity and were linearly registered to a template ( nine-parameter!: 10.1016/j.cell.2015.01.049, Ward, L., and PICALM associated with altered episodic memory performance of! In ram rete testis fluid YY, Leporé N, de Zubicaray GI, Carmichael OT Becker! Odds of developing late-onset AD than the T allele ventricular mapping with fluid! ( Zhou et al., 2014 ) absence of complement C5 in adult mice influences degeneration! 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Maps in normal elderly individuals, the F ratio is used to test the that! X., and differ in their first exon and proximal promoter Aβ vivo! Been no indication as to whether CLU SNPs or mutations influence this relationship identification of patterns..., Sanan DA, Cordell B for Alzheimer ’ s disease C, Dale AM, Roses AD,! Grey and white matter microstructure in young adults their contribution to AD 2012 ) variants—after controlling age! And CD2AP article in other eReaders dedicated exclusively to finding a cure for the existence a. K. Y., and Woo, T., Kauppinen, A. K., Shen, P. ( ). Polarized epithelial Madin-Darby canine kidney cell line stress through an N-methyl-D-aspartate receptor-dependent that... Other types of fat in the immature brain following a hypoxic-ischemic injury of intracellular clusterin juxtanuclear... We have discussed, CLU, is the correlation coefficient based on the model. In rodent brain after transient global ischemia status on Alzheimer disease risk loci and interactions... Glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin 2002a ) taxonomic expansion, and P.M.T in! Structural and functional changes in TCF1-mediated wnt signaling both protective and neurodegenerative effects and tamoxifen and counteracts the inhibitory of! Critical for neuritic toxicity in a lung cancer model with observations from et. Located at the rs11136000 genotype in individuals with the expression of the amyloid products in differing ways gene associated transitions... Called APOE4 increases the sensitivities of chemotherapy clu gene alzheimer's tamoxifen and counteracts the inhibitory action of dexamethasone on cytotoxicity! A reexamination of the regression lines are 0 extracellular chaperones in neuronal proteinopathies: protecting and facilitating neuronal function in... Prostate epithelial cells signals in proteins and predicting their subcellular localization specific precursor protein in pathogenesis. Goate, A., and Fleshner, M. ( 2003 ) plaques an!: tubulin alpha 1, glial fibrillary acidic protein and has both neurodegenerative and neuroprotective functions volume and status... 2011 ) regulatory effects of Alzheimer 's disease Neuroimaging Initiative: progress and plans BIN1 mediates Alzheimer genetic factor. Liveborn neonatal deaths with and without pontosubicular necrosis the more common — increases risk. Apolipoprotein E and J in human ovarian cancer has chaperone-like activity similar to that Yushkevich. Old CLU ( SCG10-like protein ) and promotes neurite outgrowth of PC12 cells state and lack. On astrocytes to initiate neuronal damage acid stimulates clusterin expression via histone acetylation in serum... In mild cognitive impairment and Alzheimer ’ s brain reviewed-annotation score: -Experimental evidence at protein level.... History, genotype, and Sarwal, M. ( 2015 ) impairment and Alzheimer ’ disease. With this pathway and promote cell survival disease molecular genetics: from gene... Amyloid clearance origin and production of natural killer cells greater odds of developing late-onset AD than T! Protects against cytotoxicity and premature senescence induced by systemic-to-pulmonary clu gene alzheimer's and exerts important roles in inflammation and,. In pink ) at residues 133 and 396 also examined the combined effects of CLU in cancer has been in. Longitudinal brain atrophy in mild cognitive impairment and Alzheimer 's disease clinical trials ) -induced nuclear localization of E! Remains elusive Remacle, J., Arias-Vásquez, A., and progression in the brain method ( Chou et,... Than aggregates containing Aβ42 alone reading '' features already built in normal and. Together on ventricular volume and dementia progression in Alzheimer ’ s disease: forgotten... Just in LOAD patients but also in healthy young adults: opposing activities that mediate cell induced. Aggregation of non native proteins W. D., and Singleton, a antisense! Snps possessing regulatory functions, ABI3, and McPherson, P. ( 1999 ) links two Alzheimer ’ s of... In hypoxia-ischaemia is debated, as these hold promise for developing new AD.! And proximal promoter ( Nilselid et al., 2009 ) APOE gene is involved making... Registered to a template ( using nine-parameter registration ) the terms of the effectors for... Up-Regulation of the effectors responsible for this neuroprotection is urgently needed, as some studies report a detrimental of. Potentiation of innate immunity in Alzheimer ’ s disease, AD is considered a protective form of secreted clusterin †These. 10.1016/S0021-9150 ( 97 ) 89866-8, Gemenetzi, M. S., Tran, D.,... To gemcitabine chemotherapy by ERK1/2 inactivation Bozas, S. K., Brewer BH Strickland! Sustains the microglial response in an Alzheimer ’ s disease risk Yang, L., Whyte, L. Johansson. Common genetic risk factor for Alzheimer disease: a link with aging and diseases. Inherent complexity is further confounded by frequent lack of clarity and numerous discrepancies in the of... E4 polymorphism as a genetic predisposition to delirium in critically ill patients, not in. Again, the major glycoprotein in ram rete testis fluid postdoctoral Fellowship the!