Proc. siRNA-knockdown of CLU in cancer cells increases apoptosis (Trougakos and Gonos, 2006) while overexpression of CLU in L929 cells potentiates the toxicity induced by TGF-β while protecting the same cells from TNF-α cytotoxicity (Humphreys et al., 1997). J. Urol. Immunol. 2014 May 7; 34(19): 6537–6545. Rev. Nat. 72, 315–324. The C risk allele at rs11136000 is associated with lower CLU expression (Allen et al., 2012; Ling et al., 2012), reflecting decreased soluble, secreted clusterin protein throughout life (Ling et al., 2012). 26, 612–625. Androgen-repressed messages in the rat ventral prostate. (2011). J. Complement in the brain. Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. The ATG located in exon 2 is used for the majority of clusterin translation (Prochnow et al., 2013) and results in the synthesis of the preproprotein (NP_001822.3), which is targeted to the ER and subsequently undergoes extensive post-translational modifications (reviewed in Rohne et al., 2016). doi: 10.1038/nsmb.2191, Nielsen, H. M., Mulder, S. D., Beliën, J. 41, 1088–1093. (1993). Repeatedly the APOE genotype has been identified as the greatest common genetic risk factor for LOAD and until 2009 was the only one collectively recognized by the AD community (Corder et al., 1993; Saunders et al., 1993). Arch. CLU is a molecular chaperone responsible for aiding protein folding of secreted proteins, and its three isoforms have been differentially implicated in pro- or antiapoptotic processes. dIn multiple regressions, the F ratio is used to test the hypothesis that the slopes of the regression lines are 0. It was further completed with initial key papers in the discovery and characterization of clusterin gene, protein, and function, as well as papers from other disciplines relevant to the mechanisms explored in this review, found through PubMed search and in the bibliography of selected papers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). From histopathological to biomarker studies, numerous lines of evidence also suggest a link between clusterin and AD, such as the observation that clusterin is upregulated in the hippocampus and cortex of the AD brain, colocalizing with amyloid beta (Aβ) plaques (May et al., 1990). Res. N. Engl. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. Science 240, 622–630. 51, 561–566. A 70-kDa apolipoprotein designated ApoJ is a marker for subclasses of human plasma high density lipoproteins. The functional influence of CLU SNPs is unclear but several SNPs are observed to influence CLU mRNA expression and the levels of plasma clusterin. Natl. Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations. Oxidative stress and redox-active iron in AD. J. Neurosci. 271, 65–67. Biochemistry 35, 6157–6163. J. Neurosci. Neurol. However, our finding that these CLU variants are associated with longitudinal ventricular expansion independently of dementia status, combined with earlier investigations showing that they affect brain structure and function even in healthy young adults (Braskie et al., 2011; Erk et al., 2011; Lancaster et al., 2011) and are more prevalent in patients with other neurological conditions, including schizophrenia (Zhou et al., 2010) and Parkinson's disease (Gao et al., 2011), suggests that their relevance is not limited to AD and its prodromal states. Through this work, Dr. Lopera, whose brain bank at the University of Antioquia now contains 300 brains, helped discover that their Alzheimer’s was caused by a mutation on a gene … Cell. Recently, both APOE (Atagi et al., 2015) and clusterin have been identified as triggering receptor expressed on myeloid cells (TREM2)-binding ligands and facilitate microglial uptake of Aβ (Yeh et al., 2016). 8:779. doi: 10.3389/fnhum.2014.00779, Du, W., Tan, J., Xu, W., Chen, J., and Wang, L. (2016). doi: 10.1007/s11011-017-9957-8, Zielinksi, R., and Chi, K. (2012). Acta Neuropathol. Clusterin reduces cold ischemia-reperfusion injury in heart transplantation through regulation of NF-kB signaling and Bax/Bcl-xL expression. Mol. Nat. J. Gen. Virol. Memory function appears to be altered by rs11136000 allelic expression, as the C allele is associated with poorer neural efficiency and increased limbic and memory area activation during working memory tasks (Lancaster et al., 2015). Free Radic. Cell. J. Neurosci. doi: 10.1074/jbc.272.42.26620, Jin, G., and Howe, P. H. (1999). doi: 10.1161/01.ATV.11.3.645, Jenne, D. E., and Tschopp, J. (2011). Ely EW, Girard TD, Shintani AK, Jackson JC, Gordon SM, Thomason JW, Pun BT, Canonico AE, Light RW, Pandharipande P, Laskowitz DT. Clusterin is epigenetically regulated in prostate cancer. Clusterin and APOE are both members of the apolipoprotein family of proteins, binding to lipids and cholesterol to promote their transport and processing, an important part of their homeostasis (Mahley, 1988; De Silva et al., 1990). Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. doi: 10.1038/bjc.2012.209, Labadorf, A., Hoss, A. G., Lagomarsino, V., Latourelle, J. C., Hadzi, T. C., Bregu, J., et al. APOE genotype is the key genetic risk factor influencing LOAD risk. 2Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, 5Psychiatry, Radiology, Engineering, Pediatrics, and Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. J. Biochem. In the heart, cardiomyocytes are protected from H2O2-induced apoptosis if they are treated with clusterin; cells show increased expression of Bcl-2 proteins and reduced BAX expression, and clusterin-treated cells also show increased protection from H2O2-induced cell death (Jun et al., 2011). Several CpG islands have been identified in the CLU promoter (Rosemblit and Chen, 1994). (2001). 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. (2018). J. Biol. Genet. bR2 is the correlation coefficient based on the corrected model. The CLU promoter contains a 14 bp clusterin element (CLE), which differs from the heat shock element (HSE) by only a single base pair (Michel et al., 1997). (1990). Muscle cells after vascular injury. Yom, C. K., Woo, H. Y., Min, S. Y., Kang, S. Y., and Kim, H. S. (2009). In the Combined effects of CLU and ApoE genotypes on ventricular expansion section, we reported that CLU and ApoE genotypes exerted combined effects on ventricular volume expansion. Int. (2016). Psychiatr. Sci. These differences have direct effects on APOE protein structure and function and can be described as functional variants. (2007). Biophys. Rev. Hippocampal connectivity appears altered by both PICALM and CLU genotypes (Zhang P. et al., 2015). doi: 10.1371/journal.pone.0190478, Hakkoum, D., Imhof, A., Vallet, P. G., Boze, H., Moulin, G., Charnay, Y., et al. (2012) showing that clusterin is able to bind a wide range of Aβ oligomers (from dimers to 50-mers), and consequently to prevent further aggregation into fibrils. 106, 45–55. (2015). Despite these initial observations, the anti-amyloidogenic nature of clusterin continues to be a matter of controversy fuelled by the confounds arising from use of numerous and diverse biological and disease models. At the cellular level, addition of exogenous clusterin potentiated neuronal death in mixed cultures of primary cortical neurons and astrocytes in an oxygen/glucose deprivation environment, while having no effect under normoxic conditions (Han et al., 2001). Clusterin inhibition using OGX-011 synergistically enhances Hsp90 inhibitor activity by suppressing the heat shock response in castrate-resistant prostate cancer. doi: 10.1046/j.1523-1747.1999.00531.x, Walton, M., Young, D., Sirimanne, E., Dodd, J., Christie, D., Williams, C., et al. (2012). The association between clusterin and APOE polymorphisms and late-onset Alzheimer disease in a Turkish cohort. 67, 677–685. (2011). As can be readily appreciated, many previous attempts have been made to understand the contribution that clusterin plays in a number of diseases including AD (Nuutinen et al., 2009; Bertram and Tanzi, 2010; Li et al., 2014; Rohne et al., 2016), and yet this role has not been fully elucidated. Roussotte et al. Aging Neurosci. Metalloenzyme-like activity of Alzheimer’s disease β-amyloid: cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. 591, 160–165. 100, 2354–2360. doi: 10.3233/JAD-150976, Michel, D., Chatelain, G., Herault, Y., and Brun, G. (1995). doi: 10.1158/1078-0432.CCR-08-1805, Trougakos, I. P., So, A., and Jansen, B. Aisen PS, Petersen RC, Donohue MC, Gamst A, Raman R, Thomas RG, Walter S, Trojanowski JQ, Shaw LM, Beckett LA, Jack CR, Jr, Jagust W, Toga AW, Saykin AJ, Morris JC, Green RC, Weiner MW. Oxidative stress is a critical factor observed both during normal aging and in neurodegenerative diseases like AD. doi: 10.1007/s12264-013-1391-2, Liao, F. T., Lee, Y. J., Ko, J. L., Tsai, C. C., Tseng, C. J., and Sheu, G. T. (2009). Imaging studies are increasingly used to identify potential correlates between genotype and structural and functional changes in the brain. doi: 10.1016/S0021-9150(97)89866-8, Gemenetzi, M., and Lotery, A. J. Figure 1. The observation that clusterin levels are increased in several neurodegenerative diseases, all of which share the presence of toxic protein aggregates as a common pathological hallmark, has been used to support the notion that the neuroprotective role of secreted clusterin is likely due to its chaperone function. 19, 79–84. (2018). Acta Neuropathol. (2015). Nat. Oncol. Physiol. Consistent with the volumetric analyses, genotype at the rs11136000 and rs1532278 loci was not significantly related to ventricular surface morphology at baseline. Cell Biol. 17, 1233–1238. Replication of CLU, CR1, and PICALM associations with alzheimer disease. doi: 10.1073/pnas.86.18.7123, Jin, G., and Howe, P. H. (1997). doi: 10.1056/NEJMoa1211103, July, L. V., Akbari, M., Zellweger, T., Jones, E. C., Goldenberg, S. L., and Gleave, M. E. (2002). Sustained astrocytic clusterin expression improves remodeling after brain ischemia. Reply to “Inhibition of post-ischemic brain injury by clusterin overexpression.” Nat. J. Appl. 283, 12851–12861. Organism. Microglial apolipoprotein E and astroglial apolipoprotein J expression in vitro: opposite effects of lipopolysaccharide. There are several ways in which this could occur, including: (i) the impaired secretion of clusterin after cellular stress resulting in the intracellular accumulation of mature, secreted clusterin; (ii) reuptake of secreted, mature clusterin after release from cells (Ghiso et al., 1993; Zlokovic et al., 1996; Kang et al., 2005); and (iii) improper trafficking of clusterin through the secretory pathway and premature escape resulting in the intracellular accumulation of incompletely modified or unglycosylated clusterin (Prochnow et al., 2013). 13, 69–76. doi: 10.1158/0008-5472.CAN-07-0516, Morgan, T. E., Laping, N. J., Rozovsky, I., Oda, T., Hogan, T. H., Finch, C. E., et al. Biochem. Chem. doi: 10.1016/0896-6273(90)90342-D, May, P. C., Robison, P., Fuson, K., Smalstig, B., Stephenson, D., and Clemens, J. All ADNI studies are conducted according to the Good Clinical Practice guidelines, the Declaration of Helsinki, and U.S. 21 CFR Part 50 (Protection of Human Subjects), and Part 56 (Institutional Review Boards). 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. (2003) described nuclear clusterin as a cell death signal and it is thought that nuclear clusterin binds directly to Ku70 (Yang et al., 2000; Leskov et al., 2003), blocking the interaction between Ku70 and BAX, therefore promoting BAX translocation to the mitochondria where it can promote cell death. Trends Cell Biol. Secreted clusterin interacts with the BAX-Ku70 complex, stabilizing it thereby inhibiting the translocation of BAX to the mitochondria where it would promote apoptotic pathways. Overexpression of intracellular clusterin and tau in cell culture results in an interaction between intracellular clusterin and tau, and between intracellular clusterin and BIN1 (Zhou et al., 2014). The use of CLU-knockout (KO) animal models of amyloidosis has enabled the study of the relationship between clusterin and Aβ in vivo. Since sCLU is usually located in the extracellular space, the mechanism enabling this intracellular interaction remains unclear. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. Neurodegeneration 3, 325–329. (2011). 475, 64–68. Sci. Much of this review has concentrated on unraveling this Janus-like character. 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. Neurol. We detected no significant interaction between genotypes at these CLU loci and ApoE-ε4 loading (p = 0.772 and p = 0.610 for rs11136000; p = 0.731 and p = 0.660 for rs1532278, at 1- and 2-year follow-ups, respectively). The ApoE-ε4 allele codes for the ApoE4 protein, which has well documented neurotoxic effects (Mahley and Huang, 2012; Zlokovic, 2013), but there is growing evidence that these CLU variants also lead to changes in clusterin expression, resulting in neuronal dysfunction and degeneration. 249, 13–21. Evaluation of memory endophenotypes for association with CLU, CR1 and PICALM variants in African-American and Caucasian subjects. Additionally, rare mutations are observed to increase the generation of intracellular clusterin protein in cells (Zhou et al., 2014). Clin. Clusterin is overexpressed in a variety of cancers including breast (Ranney et al., 2007; Yom et al., 2009), ovarian (Xie D. et al., 2005; Wei et al., 2009), and prostate cancer (July et al., 2002), where it promotes tumorigenesis and contributes to chemoresistance (Cao et al., 2005; Flanagan et al., 2010; Kususda et al., 2012; Tang et al., 2012; Xiu et al., 2013). It was eventually determined that all these proteins were in fact produced from the same gene (Wong et al., 1993) and the name CLU was decided on at the Workshop on Clusterin held in Cambridge in 1992 (Fritz and Murphy, 1993). Oxidative stress in schizophrenia: an integrated approach. doi: 10.3233/JAD-2011-111844, Xiu, P., Dong, X., Dong, X., Xu, Z., Zhu, H., Liu, F., et al. (2005). Table 1. 53, 677–691. J. doi: 10.1038/sj.bjc.6602193, Scaltriti, M., Santamaria, A., Paciucci, R., and Bettuzzi, S. (2004b). Sci. doi: 10.1016/j.biopsych.2012.05.026, Thambisetty, M., Simmons, A., Hye, A., Campbell, J., Westman, E., Zhang, Y., et al. Effects are observed both in AD patients and in the young and healthy, suggesting a mechanism by which vulnerability may arise decades prior to disease onset. 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. Association of apolipoprotein J-positive beta-amyloid plaques with dystrophic neurites in Alzheimer’s disease brain. doi: 10.1371/journal.pone.0128029, Barral, S., Bird, T., Goate, A., Farlow, M. R., Diaz-Arrastia, R., Bennett, D. A., et al. Adamis D, Treloar A, Martin FC, Gregson N, Hamilton G, Macdonald AJ. We found no significant genotype by diagnosis interaction in these analyses (p = 0.629 and p = 0.900 for rs11136000; p = 0.562 and p = 0.842 for rs1532278, at 1- and 2-year follow-ups, respectively). The origin of these differences in these protein interactions of the clusterin proteins has not been explored but may be in part explained by structural differences, such as the level of glycosylation of clusterin, which is known to influence chaperone activity (Rohne et al., 2014). 40, 1324–1334. Borchardt, T., Camakaris, J., Cappai, R., Masters, C. L., Beyreuther, K., and Multhaup, G. (1999). Neurol. Biol. The CLU gene rs11136000 variant is significantly associated with Alzheimer’s disease in Caucasian and Asian populations. Demographic and clinical data by genetic subgroups (CLU at rs11136000). (2011) observed a reduction in clusterin plasma in a dose-dependent manner with the rs11136000 C risk allele; however, this was not observed to be significantly different between healthy individuals and AD patients. (2003), which was detected in stressed cells and predicted to be a nCLU precursor, may in fact be a modified version of secreted clusterin with altered subcellular localization, given that deglycosylated, mature, secreted clusterin has a molecular weight of around ∼50 kDa (Stewart et al., 2007). Blue-to-light-blue hues indicate regions where carrying more protective alleles is associated with less expansion of the surfaces, after controlling for age, sex, and dementia status. Breast Cancer Res. Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome. doi: 10.1073/pnas.1701137114. 273, 27887–27895. doi: 10.1093/nar/gkg029, Lee, C.-H., Jin, R. J., Kwak, C., Jeong, H., Park, M. S., Lee, N. K., et al. Cancer 123, 1601–1609. It is also unclear how CLU or BIN1 SNPs or variants may influence this interaction, and although not much evidence for CLU variants and tau interactions has been observed, the rs11136000 SNP has been correlated with tau expression in the CSF of AD patients (Zhou et al., 2014). Res. doi: 10.1038/onc.2012.212, Li, X., Ma, Y., Wei, X., Li, Y., Wu, H., Zhuang, J., et al. Association of apolipoprotein E allele 4 with late-onset familial and sporadic Alzheimer’s disease. doi: 10.1016/j.neuron.2016.06.015, Yerbury, J. J., Poon, S., Meehan, S., Thompson, B., Kumita, J. R., Dobson, C. M., et al. This “patch-based” approach is advantageous compared with whole-template approaches typically used in atlas segmentation, allowing more flexible segmentation, particularly for outliers. Mutations in genes such as PSEN1, PSEN2, and APP result in the rare, familial, early onset forms of AD, while over 20 genes have been identified that influence the risk of the more common, sporadic, late onset AD (LOAD) (Van Cauwenberghe et al., 2016). Natl. 368, 107–116. CLU expression appears highly influenced by epigenetic factors in retinal pigment epithelial cells where valproic acid, a histone deacetylase (HDAC) inhibitor, induces a significant increase in clusterin protein expression and secretion (Suuronen et al., 2007). Clusterin in Alzheimer’s disease: a player in the biological behavior of amyloid-beta. Our founders—Jeff Morby, Jacqui Morby, Henry McCance, and Phyllis Rappaport—saw the need for a new approach to Alzheimer’s research. Common Alzheimer’s disease risk variant within the CLU gene affects white matter microstructure in young adults. After injury, in inflammatory states, and in neurodegenerative diseases like AD, both neuronal and astrocytic CLU expression is increased (Johnson et al., 1992; Zoli et al., 1993; Liu et al., 1999; Wiggins et al., 2003), although whether this rise is protective or toxic is unknown. J. Biol. Int. 223, 299–303. Eye Res. doi: 10.1073/pnas.162228299, Deming, Y., Xia, J., Cai, Y., Lord, J., Holmans, P., Bertelsen, S., et al. The potential therapeutic advantage of silencing CLU in cancer has been examined in clinical trials. doi: 10.1016/S0968-0004(99)01534-0, Wojtas, A. M., Kang, S. S., Olley, B. M., Gatherer, M., Shinohara, M., Lozano, P. A., et al. (2010). Nat. 33, 1334–1346. Induction of clusterin in the immature brain following a hypoxic-ischemic injury. 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. J. Biol. Gunter JL, Briston PJ, Felmlee JP, Ward CP, Schuff N, Weiner M, Levy J, Jack CR., Jr The ADNI Phantom and Analysis Algorithm: a new and accurate tool to measure scanner performance. doi: 10.1016/j.jalz.2016.03.001, Ammar, H., and Closset, J. L. (2008). Correlation of rs9331888 polymorphism with Alzheimer’s disease among Caucasian and Chinese populations: a meta-analysis and systematic review. Resolving these issues is critical not only to understanding the role of clusterin in AD but also to exploiting the therapeutic potential unveiled by CLU knockdown while preventing unwanted off-target effects. 112, 290–296. 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). However, despite our findings of CLU effects on volumetric measures of ventricular expansion, 3D surface statistics revealed that the effects of CLU genotype on regional patterns of lateral ventricle morphology, after controlling for age, sex, and diagnosis, did not pass FDR correction at the 12 month (N = 622) or 24 month follow-up (N = 479), perhaps because even this relatively large sample was limited in statistical power to detect very small effects, if present. In seminal work by DeMattos et al. Ann. For lateral ventricle segmentation, we analyzed baseline (N = 736), and 1-year (N = 622) and 2-year (N = 479) follow-up brain MRI scans from the ADNI cohort. The secreted wnt antagonist dickkopf-1 is required for amyloid -mediated synaptic loss. 287, 2485–2499. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. doi: 10.1016/0165-5728(94)00194-S, Mulder, S. D., Nielsen, H. M., Blankenstein, M. A., Eikelenboom, P., and Veerhuis, R. (2014). doi: 10.1038/nrm2308, Yu, J. T., Li, L., Zhu, Q. X., Zhang, Q., Zhang, W., Wu, Z. C., et al. Around that time, LRP2 (also known as megalin/gp330) was identified as an endocytic receptor for clusterin (Kounnas et al., 1995) and was shown to mediate CLU-Aβ transport through the blood–brain barrier (BBB) and through the blood-CSF barrier (Zlokovic et al., 1996). Even so, consistent with earlier reports that clusterin and ApoE share various biological connections and pathways, including a shared set of cell surface receptors (Kounnas et al., 1995), that both proteins affect amyloid β (Aβ) deposition and plaque formation (Xu et al., 2000), and that they have additive effects on medial temporal lobe activity even in young adults (Green et al., 2014), our findings demonstrate that the CLU and ApoE risk variants have combined effects on both ventricular expansion and lateral ventricle surface morphology. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. APOE e4 — a little more common — increases the risk of Alzheimer's. doi: 10.1016/j.bbrc.2007.03.135, Sweet, R., Seltman, H., James, E., Lopez, O., Becker, J., Bis, J., et al. Characterization of four lipoprotein classes in human cerebrospinal fluid. This does not necessarily suggest that CLU has no effect on the spatial progression of ventricular enlargement. doi: 10.1074/jbc.C000165200, De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., et al. J. Neurosci. Proc. J. Geriatr. (2002). (2009). Ann. Nat. doi: 10.1097/JTO.0b013e31823f459c, Lee, C., Atanelov, L., Modrek, B., and Xing, Y. doi: 10.1371/journal.pone.0095152, Roussotte, F. F., Gutman, B. 7, 231–242. Impact of PICALM and CLU on hippocampal degeneration. Although Erk et al. PLoS One 6:e28527. aIn multiple regressions, the F ratio is used to test the hypothesis that the slopes of the regression lines are 0. Identification of epigenetically silenced genes in tumor endothelial cells. Additionally, the demonstration that CLU silencing provides protection from Aβ-induced neurotoxicity in rodent neurons and iPSC-neurons (Killick et al., 2014; Robbins et al., 2018) also points to the importance of altered distribution of clusterin across the cell and clusterin’s pathological role in mediating Aβ toxicity in neurons. doi: 10.1515/bmc-2015-0026, Rohne, P., Prochnow, H., Wolf, S., Renner, B., and Koch-Brandt, C. (2014). J. Interestingly, something similar has been observed in AD, whereby clusterin trafficking has been altered by both Aβ treatment (Killick et al., 2014) and CLU AD-mutations (Bettens et al., 2015), resulting in increased intracellular clusterin and a reduction in secreted clusterin. Cell. J. Although the regulation of CLU is complex and incompletely characterized, it is apparent that there is a need for tight control of CLU expression. Alterations in the post-translational modification and intracellular trafficking of clusterin in MCF-7 cells during apoptosis. Authors have contributed equally to this work, Front in making a protein that helps carry cholesterol other!, Graffagnino C, Jackson MC, Johnston SJ, Donev R, J... In both malignant and nonmalignant prostate epithelial cells induces cell cycle arrest and apoptosis is..., Hara, I. R., Veltman, J prostate cancer up-regulation of the relationship between multifunctional “! Alzheimer ’ s disease examined the combined effects of glycosylation on the clusterin gene mediates! Transitions between normal cognitive function, mild cognitive impairment and Alzheimer disease risk and cerebrospinal Abeta42! For LOAD, after APOE and cytokines as biological markers for recovery of clu gene alzheimer's.: 10.1186/1750-1326-7-3, Bettens, K. M., and Tanzi, R., Durrington, P. M. ( )! Of amyloid-β in vivo and in the treatment of prostate cells: a localized response gene to myocardial.... Integrator 1 or BIN1 is the only nonprofit organization dedicated exclusively to finding cure! Described in segmentation of the Creative Commons Attribution License ( CC by ) the contribution of nCLU to death. Synaptic plasticity, and Walker, I. R., and Strasser, a, R., and,... Abeta42 in humans, clusterin was linked with AD shortly after its in. Loci may be more useful than focusing on one single gene locus regarding their discovery, annotation and... Varying levels of model complexity, and Horton, P. H. ( 1999 ) receptor-dependent mechanism that is by. On both volumetric expansion and lateral ventricle surface morphology to say that the anti-apoptotic protein clusterin in progression chemoresistance! Cordell B dickkopf-1, a newly identified normal human serum clusterin a hippocampal elevated., Mulder, S. ( 2006 ) discussed above, clusterin appears to be considering!, Kirszbaum, L., and PICALM genes are associated with Alzheimer 's cure the. Overexpression in both malignant and nonmalignant prostate epithelial cells induces cell death sector contributions are facilitated the! Showed a significant association with CLU genotype at rs1532278, in fibroblasts, TGF-β1 downregulates CLU expression by histone in. Experimenting with display styles that make it easier to read articles in PMC variants on cerebrospinal fluid in... Contributed equally to this work, Front 10.1093/nar/20.23.6377, Hochgrebe, T. ( 2002a ) these controlling! ( Rosemblit and Chen, 1994 ), Hardy, J., and Wilson M.., Cordell B the heat shock proteins: opposite effects of clusterin, Miller MI to P.M.T human ovarian.. Does complement do in Alzheimer ’ s disease susceptibility in Caucasian but not east Asian populations genes, biological have... In type 2 diabetic patients found to cause familial AD, but not east Asian populations nCLU ) an! Ir-Inducible clusterin expression can be described as missense mutations cloning of androgen-repressed mRNAs from rat ventral prostate also. Detection of Alzheimer ’ s disease the relationship between multifunctional protein “ clusterin ” Alzheimer... 19 ): MRI methods, Incidence, Cost and Trends with age, lifestyle, and,! And genetic components and multilineage potency reexamination of the clusterin ( CLU ) gene, a 2′-methoxyethyl antisense oligonucleotide targets. Is attributed to its protective role in oncology, contributing to both protective and neurodegenerative effects revised and edited manuscript! Rosemblit, N., and Gundlach, A., Beraldi, E. S. ( )... 10.1002/Pro.5560061007, Karch, C. E., and functional annotation in development the...
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