East Asian Arch Psychiatry 2011;21:79-84


Two Polymorphisms of RCAN1 Gene Associated with Alzheimer’s Disease in the Chinese Han Population
KG Lin, M Tang, YB Guo, HY Han, YH Lin

Dr Kangguang Lin, MMed, Department of Geriatric Psychiatry, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou 510370, PR China.
Dr Muni Tang, MD, Department of Geriatric Psychiatry, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou 510370, PR China.
Dr Yangbo Guo, MD, Department of Geriatric Psychiatry, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou 510370, PR China.
Dr Haiying Han, Department of Geriatric Psychiatry, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou 510370, PR China.
Ms Yuhua Lin, Department of Molecular Genetics Laboratory, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, Guangzhou 510370, PR China.

Address for correspondence: Dr Kangguang Lin, Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical College, 36 Mingxin Road, Fangchun District, Guangzhou, Guangdong Province 510370, PR China.
Tel: (86-20) 8189 1425; Fax: (86-20) 8189 1391; Email: linkangguang@163.com

Submitted: 23 November 2010; Accepted: 15 February 2011

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Objective: Regulator of calcineurin 1 (RCAN1) gene is a regulator on the activity of calcineurin and was reported to be overexpressed in Alzheimer’s disease. The aim of this study was to evaluate several polymorphisms of RCAN1, located in the probable promoter region of RCAN1-4 and around the exonic splicing enhancer motifs of RCAN1, in a cohort of Chinese late-onset Alzheimer’s disease.

Methods: A pilot case-control study was conducted in 142 Alzheimer’s disease patients and 99 non- demented controls from Chinese Han population. Fragments of the RCAN1 including 5 polymorphisms (rs71324311, rs3831376, rs10550296, rs8135540, rs78899361) were amplified and sequenced.

Results: In our sample, 2 polymorphisms (rs71324311 and rs10550296) were associated with Alzheimer’s disease. Of these 2 polymorphisms, the heterozygous deletion genotype of rs71324311 was more prevalent in non-demented controls than in those with Alzheimer’s disease (4% vs. 0%), indicating a slight protective role (Fisher’s exact test, p = 0.03; crude odds ratio = 0.96, 95% confidence interval = 0.92-0.99). There was only a trend towards a significant difference in the distributions of genotypes of rs10550296 between 2 groups (χ2 = 1.93; p = 0.17; crude odds ratio = 1.44, 95% confidence interval = 0.85-2.41). However, logistic regression analysis showed that the age-, gender- and apolipoprotein E ε4- adjusted odds ratio of Alzheimer’s disease with rs10550296 heterozygous deletion genotype was 2.11 (χ2 = 4.42; p = 0.04; 95% confidence interval = 1.05-4.20).

Conclusions: Regarding Alzheimer’s disease susceptibility in Chinese Han population, our data suggested a protective role for the rs71324311 heterozygous deletion genotype and a risk role from the rs10550296 heterozygous deletion genotype.

Key words: Alzheimer disease; Association; Calcineurin; Polymorphism, genetic


目的:钙调神经磷酸酶1 (RCAN1)基因的调节物用作调节钙调神经磷酸酶活动;文献也记载关於在阿兹海默氏症中发现这种基因过份表达的报告。本研究旨在於一组华籍迟发性阿兹海默氏症患者中,评估可能於基因启动区RCAN1-4和RCAN1外显子剪接增强子基序附近发现的基因几种多态性。

方法:这项试验性病例对照研究共纳入142名华籍阿兹海默氏症患者和99名非患者作对照组,并将包括5种多态性的RCAN1片段(rs71324311、rs3831376、rs10550296、rs8135540、 rs78899361)放大和排列作分析。

结果:在样本当中,其中两个单核苷酸多态性位点(rs71324311和rs10550296)与阿兹海默氏症相关,而属异型接合缺损型的rs71324311在对照组所占的比重较阿兹海默氏症患者为多(4%对0%),这表明它担当轻微的防护角色(Fisher’s exact test,p = 0.03;未经调整比对值 = 0.96,95%置信区间 = 0.92-0.99)。两组间的rs10550296基因型分佈有明显分别(χ2 = 1.93;p = 0.17,未经调整比对值 = 1.44,95%置信区间 = 0.85-2.41)。不过,逻辑迴归分析显示,带有异型接合缺损型rs10550296基因的阿兹海默氏症患者,其经年龄、性别和载脂蛋白E ε4调整的比对值为2.11(95%置信区间 = 1.05-4.20;χ2 = 4.42;p = 0.04)。




Late-onset Alzheimer’s disease (LOAD) is a genetically complex and heterogeneous disorder. A hereditary basis for Alzheimer’s disease (AD) was estimated to about 60% to 80%.1 Nearly all subsequent studies confirmed that ε4 allele of apolipoprotein E (ApoE) as a genetic susceptibility factor for LOAD, since it was first found by means of genetic linkage analysis in 1991.2 The ApoE ε4 allele has been estimated to account for only 20% of the genetic risk in LOAD, and recent studies including both the candidate gene and genome-wide approaches have found several risk genes for LOAD3 (http://www.alzgene.org). Although highly estimated, all the candidate genes reported might not explain over 50% of all LOAD inheritance, which is in contrast to what is known about the genetics of other complex diseases such as age-related macular degeneration.4 In other words, there is a substantial proportion of unaccounted genetic risk for LOAD, even after genome-wide association studies.5

The human regulator of calcineurin 1 gene (RCAN1, also called DSCR1, Adapt78, MCIPI, or calcipressin 1) is located on chromosome 21q22.12.6 RCAN1 is a regulator on the activity of calcineurin and observed to be overexpressed both in the brains of Down’s syndrome patients and AD patients.7,8 Overexpression of RCAN1 contributed to hyperphosphorylated tau,9,10 reduced synaptic vesicles,11 and abnormal synaptic morphology.12 However, lack of RCAN1 displayed severe learning deficits in drosophila,13 memory defects, and impaired late-phase long-term potentiation in mice.14 Furthermore, Porta et al15 found that RCAN1 modulated neuronal cell survival and death pathways depending on the RCAN1 dosage.

The RCAN1 gene consists of 7 exons, which can be alternatively spliced to produce different mRNA isoforms, of which RCAN1-1 and RCAN1-4 are the 2 major observed forms.16 Yang et al17 found that the upstream of exon 4 contained a cluster of nuclear factor of activated T-cells (NFAT)–binding motifs that contributed to the alternative promoter usage. The promoter of RCAN1-4 is activated by calcineurin that RCAN1 can inhibit in return, which formed a negative feedback circuit. Different CCAAT / enhancer-binding protein β (C/EBP β) isoforms and NFAT isoforms can activate transcription of RCAN1-4 through binding to conserved C/EBP β– binding sites located on the promoter region.18,19 There are several polymorphisms, including (1) rs78899361 (g.21561755C>T); (2) rs8135540 (g.21561747A>C); (3) rs10550296 (g.21561498_21561501del4); (4) rs3831376 (g.21561495_21561498del4); and (5) rs71324311 (g.21561494_21561497del4)] located in the suggested promoter region. Exonic splicing enhancer (ESE) finder (Cold Spring Harbor Laboratory, New York, US) was used to test whether these polymorphisms had the ability to affect or act as an ESE and found polymorphisms around several ESE motifs in the region (range contig position from 21561001 to 21561901). Although highly estimated, some of these polymorphisms might have the potential to interfere with the splicing of RCAN1 and expression of RCAN1-4. In addition, rs8135540 is a tag single-nucleotide polymorphism (SNP) and the use of common tag SNPs in association studies assumes the common disease–common variant hypotheses.20

Despite RCAN1 being a candidate gene on both functional and positional grounds, there are no studies so far considering the genetic association of RCAN1 and AD. Our aim was to study the possible genetic association between the polymorphisms located in the RCAN1 (the probable promoter for RCAN1-4) and AD.



As shown in Table 1, the study group consisted of 142 clinically diagnosed AD patients and 99 non-demented elderly controls (NECs). Patients and NECs were selected from old folks’ homes and urban and rural communities in the survey area of dementia epidemiology in Guangzhou from 2001 to 2002. Among the patients, 67 were chosen from the Guangzhou Psychiatric Hospital. The diagnosis of AD was based on criteria given in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition,21 as well as the National Institute of Neurological and Communicative Diseases and Stroke / Alzheimer’s Disease and Related Disorders Association.22 All patients examined had late onset of AD (defined as onset at age ≥ 65 years). In addition, they had no family history of dementia, psychotic disorder, or medical history of neurological disease. All AD patients and NECs were unrelated Chinese Han. Informed consent was obtained from each subject directly or from his / her guardian. The protocol for this study was approved by the respective Institutional Ethical Committees.

Marker Selection and Genotyping

Information about SNP was obtained from 2 open databases: National Center for Biotechnology Information dbSNP (Build 135 http://www.ncbi.nlm.nih.gov/snp/]) and International HapMap Project (Rel 28 PhasesⅡ+Ⅲ, on [NCBI B36 assembly, dbSNP b126 [http://hapmap.ncbi.nlm.nih.gov/]).

Genomic DNA was extracted from whole blood according to standard procedures. Genotyping analysis of ApoE was performed as previously described.23 The ≈540-bp genomic segment for the promoter position of RCAN1-4 (-870 to -330 bp) including polymorphisms (rs78899361, rs8135540, rs10550296, rs3831376, rs71324311) was produced using the following primers: 5’-gctactcagacaacacgctcct-3’ and 5’-cctctggcataaatgggtt-3’. The product was sequenced with an ABI 3700 sequencer and a BigDyeTM Terminator V3.0 cycle Sequencing (Applied Biosystems, US) and the polymorphisms were detected by Mutation Surveyor (Applied Biosystems Genetic Analyzers, US), and ambiguities resolved by visual observation of peak heights (Figure).

Data Analyses

Genotypic and allelic frequencies were calculated, and the Hardy-Weinberg equilibrium was tested with a dedicated software program (utility programs for analysis of genetic linkage by The Rockefeller University, USA [http:// linkage.rockefeller.edu/]). The χ2 test was applied to compare genotypic and allelic frequencies in cases and controls. Logistic regression analysis was used to explore the main effect, confounding, effect modification, and interactions between age, gender, and ApoE and RCAN1 genotypes. Linkage disequilibrium (LD) was estimated by SHEsis software.24 The ESE finder was used for the ESE test (http://rulai.cshl.edu/tools/ESE/). For all of the tests, the criterion for statistical significance was set at p ≤ 0.05.


This study identified a novel variation (CTCA/-, NT_01151211: g21561493-21561496del4), all of which were heterozygous deletions (het_del). The 3 bp (thymine- cytimidine-adenine) overlap of this novel variation with rs71324311 suggested their complete joint occurrence, which was considered the same polymorphism as rs71324311. The distributions of rs71324311, rs10550296 and rs8135540 were in Hardy-Weinberg equilibrium (p > 0.05). Table 2 shows both genotypic and allelic associations in the cases and controls. There were 4 subjects carrying the rs71324311 het_del genotype in NEC, but none in the AD cases. The frequency of the het_del genotype (4%) and the del allele (2%) in controls were significantly higher than that (0%, 0% respectively) in AD cases (Fisher’s exact test, p = 0.03; crude odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.92-0.99 vs. p = 0.03; crude OR = 0.98, 95% CI = 0.96-1.00).

No significant difference was found in the distributions of alleles or genotypes of rs10550296 and rs8135540 between AD cases and NECs (Table 2). However, we did find a trend towards a significant difference in the distributions of genotypes of rs10550296 between 2 groups (χ2 = 1.93; p = 0.17; crude OR = 1.44, 95% CI = 0.85-2.41). Then, the logistic regression analysis was used to explore the main effect, confounding, effect modification, or interactions between age, gender, and ApoE and rs10550296 or rs8135540 genotypes. rs10550296 (by del allele), rs8135540 (by genotypes), ApoE (by ε4 allele) genotypes and gender were categorical variables, while age was included as a continuous variable (1-year intervals). The analysis revealed that the het_del carriers of rs10550296 had an adjusted OR of 2.11 (95% CI = 1.05-4.20; χ2 = 4.42; p = 0.04) to have AD compared to homozygotes of the major allele. We further tested whether there were statistical interactions between rs10550296 genotype and age (categorised age ≤ 72 years and > 72 years), gender, and ApoE genotype, but no significant interaction was found (data not shown). The analysis also suggested rs8135540 had neither influence on the risk of developing AD (χ2 = 0.59; p = 0.44; adjusted OR = 1.17, 95% CI = 0.78-1.75) nor the interaction between rs8135540 genotype and age, gender and ApoE genotypes (data not shown).

There was no variation on rs3831376 and rs78899361 among the 142 AD cases and 99 NECs. Because of these distributions, the case-control analysis was not pursued on these 2 polymorphisms.

The two markers (rs10550296 and rs8135540) were found not to be in LD with each other (D’ = 0.06, r2 < 0.001, Fisher’s exact test, p = 0.86) in the control group (rs71324311 was not included because of low allelic frequency).


RCAN1 was originally discovered as an oxidant stress- inducible gene and played a critical role in oxidative stress.25,26 In fact, many studies indicated that oxidative stress in AD patient brains was a very early event and served as an initiator. In AD, this also included lipid peroxidation preceded amyloid plaque formation, increased antioxidative enzyme activities, and tau protein phosphorylation.27-31 In addition, the importance of RCAN1 protein in locomotor activity and working memory was recognised by some studies.32,33 In our studies, we found preliminary evidence of 2 RCAN1 polymorphisms associated with AD, of which rs71324311 het_del genotype suggested a protective factor with a slight OR of 0.96. The rs10550296 het_del genotype conferred a moderate AD risk with an OR of 2.11. Both of these 2 variants were located in the promoter region of RCAN1-4 and the putative regulatory region,17,19 which might have a potential influence on the transcription of RCAN1-4. Ermak et al34 reported that RCAN1 mRNA levels in AD postmortem brain samples was 2-fold higher than that in age-matched controls. We speculated that these polymorphisms played their roles in the risk of developing AD through influencing transcription or the splicing of RCAN1. However, another study8 found that RCAN1-1 (but not RCAN1-4) was overexpressed in AD postmortem brains. The possibilities are that the level of RCAN1-4 in the early stage of AD could not be detected in the postmortem brain samples, which might play a vital role in the oxidative stress in early AD, or the amount of RCAN1-4 in different cellular localisation could not be evaluated by means of western blotting. In addition, genetic linkage studies have provided evidence for both LOAD and familial AD susceptibility locus on this 21q region.35,36 Thus, it is possible that the 2 tested polymorphisms are LD with a ‘real risk locus’ either in RCAN1 itself or in another gene nearby. However, the functional significance of these 2 polymorphisms remains unknown. Moreover, unravelling the mechanisms by which the het_del genotype of these 2 polymorphisms are associated with lower or higher risks for AD will depend on future functional studies. Interestingly, the frequency of rs71324311 het_del genotype (4%) was low (only 4 out of 99 NECs were heterozygous), and none of the AD cases carried the genotype. Further larger sample studies are needed to test whether this could be a marker for non-AD status. In addition, the Chi-square test only showed a trend towards a difference, while the logistic regression analysis found an adjusted OR of 2.11 for AD risk in rs10550296 het_del carriers. This implied that confounding factors such as age, gender and ApoEε4 allele should be considered while studying the role of rs10550296 in the risk of AD.

We found no statistically significant association between rs8135540 and AD, even though we adjusted for age, gender and the ApoEε4 allele. The rs8135540 is a tag SNP (A to C substitution). If a tag SNP was not associated with functional polymorphism or a ‘real risk locus’, it would not be easy to reveal the association. In our samples, the rs8135540 was not in significant LD with rs10550296. Our studies suggested that rs8135540 might not play a major role in AD, since the 38% frequency of the variant alleles in the AD cases were unexpectedly similar to the 37% frequency in NECs. In addition, we observed a higher frequency of rs8135540 C allele in our study than the 20% found in the HapMap project. This implied regional differences in Chinese populations, since our samples represented the southern Chinese Han population, while the HapMap Project recruited 45 unrelated subjects from Beijing.

A limitation to this study was that we used single direction sequence traces. For instance, it was hard to genotype rs8135540 if a deletion mutation happened upstream. Although the Mutation Surveyor reported an accuracy of 95% when conducting single direction analysis, rs8135540 could not be genotyped in 5 subjects and in a few subjects there were ambiguities due to confusing signals. The chance of a genotyping error for rs8135540 was much higher than that for other tested polymorphisms. Another limitation is related to the modest sample size. Although our sample size had the ability to detect statistically significant differences between rs71324311 and rs10550296 and AD, the low frequency of the minor alleles might have increased the risk for a false-positive result. Therefore a larger study sample is required to confirm these findings.

In conclusion, the present study is the first attempt for an association analysis of RCAN1 polymorphism with AD. Moreover, we found associations with 2 polymorphisms in our samples. Indeed, RCAN1 was considered to be pathophysiologically related to AD. Further studies evaluating these polymorphisms and other RCAN1 variants in large samples of AD patients in different ethnic population would be of interests and are needed to clarify the role of RCAN1 polymorphism in AD.


This work was supported by Guangzhou Medical Science and Technology Projects (Project No: 2008-YB-101).


  1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168-74.
  2. Pericak-Vance MA, Bebout JL, Gaskell PC Jr, Yamaoka LH, Hung WY, Alberts MJ, et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991;48:1034- 50.
  3. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007;39:17-23.
  4. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 2010;107:7401-6.
  5. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747-53.
  6. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, et al. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J 2007;21:3023-8.
  7. Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 2000;9:1681-90.
  8. Harris CD, Ermak G, Davies KJ. RCAN1-1L is overexpressed in neurons of Alzheimer’s disease patients. FEBS J 2007;274:1715-24.
  9. Garver TD, Kincaid RL, Conn RA, Billingsley ML. Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. Mol Pharmacol 1999;55:632-41.
  10. Poppek D, Keck S, Ermak G, Jung T, Stolzing A, Ullrich O, et al. Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. Biochem J 2006;400:511-20.
  11. Keating DJ, Dubach D, Zanin MP, Yu Y, Martin K, Zhao YF, et al. DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer’s disease. Hum Mol Genet 2008;17:1020-30.
  12. Chang KT, Min KT. Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc Natl Acad Sci U S A 2009;106:17117-22.
  13. Chang KT, Shi YJ, Min KT. The Drosophila homolog of Down’s syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc Natl Acad Sci U S A 2003;100:15794-9.
  14. Escorihuela RM, Vallina IF, Martínez-Cué C, Baamonde C, Dierssen M, Tobeña A, et al. Impaired short- and long-term memory in Ts65Dn mice, a model for Down syndrome. Neurosci Lett 1998;247:171-4.
  15. Porta S, Serra SA, Huch M, Valverde MA, Llorens F, Estivill X, et al. RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration. Hum Mol Genet 2007;16:1039-50.
  16. Fuentes JJ, Pritchard MA, Estivill X. Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics 1997;44:358-61.
  17. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, et al. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 2000;87:E61-8.
  18. Wu H, Kao SC, Barrientos T, Baldwin SH, Olson EN, Crabtree GR, et al. Down syndrome critical region-1 is a transcriptional target of nuclear factor of activated T cells-c1 within the endocardium during heart development. J Biol Chem 2007;282:30673-9.
  19. Oh M, Dey A, Gerard RD, Hill JA, Rothermel BA. The CCAAT/ enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4. J Biol Chem 2010;285:16623-31.
  20. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003;33:177-82.
  21. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.; American Psychiatric Association; 1994.
  22. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS- ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939-44.
  23. Lin K, Tang M, Han H, Guo Y, Lin Y, Ma C. GAB2 is not associated with late-onset Alzheimer’s disease in Chinese Han. Neurol Sci 2010;31:277-81.
  24. Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005;15:97-8.
  25. Crawford DR, Leahy KP, Abramova N, Lan L, Wang Y, Davies KJ. Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch Biochem Biophys 1997;342:6-12.
  26. Ermak G, Harris CD, Davies KJ. The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J 2002;16:814-24.
  27. Apelt J, Bigl M, Wunderlich P, Schliebs R. Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int J Dev Neurosci 2004;22:475-84.
  28. Chen L, Na R, Gu M, Richardson A, Ran Q. Lipid peroxidation up- regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease. J Neurochem 2008;107:197-207.
  29. Casado A, Encarnación López-Fernández M, Concepción Casado M, de La Torre R. Lipid peroxidation and antioxidant enzyme activities in vascular and Alzheimer dementias. Neurochem Res 2008;33:450-8.
  30. Su B, Wang X, Lee HG, Tabaton M, Perry G, Smith MA, et al. Chronic oxidative stress causes increased tau phosphorylation in M17 neuroblastoma cells. Neurosci Lett 2010;468:267-71.
  31. Ebenezer PJ, Weidner AM, LeVine H 3rd, Markesbery WR, Murphy MP, Zhang L, et al. Neuron specific toxicity of oligomeric amyloid-β: role for JUN-kinase and oxidative stress. J Alzheimers Dis 2010;22:839-48.
  32. Sanna B, Brandt EB, Kaiser RA, Pfluger P, Witt SA, Kimball TR, et al. Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo. Proc Natl Acad Sci U S A 2006;103:7327-32.
  33. Hoeffer CA, Dey A, Sachan N, Wong H, Patterson RJ, Shelton JM, et al. The Down syndrome critical region protein RCAN1 regulates long- term potentiation and memory via inhibition of phosphatase signaling. J Neurosci 2007;27:13161-72.
  34. Ermak G, Morgan TE, Davies KJ. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer’s disease. J Biol Chem 2001;276:38787-94.
  35. van Duijn CM, Hendriks L, Farrer LA, Backhovens H, Cruts M, Wehnert A, et al. A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21. Am J Hum Genet 1994;55:714-27.
  36. Myllykangas L, Wavrant-De Vrièze F, Polvikoski T, Notkola IL, Sulkava R, Niinistö L, et al. Chromosome 21 BACE2 haplotype associates with Alzheimer’s disease: a two-stage study. J Neurol Sci 2005;236:17-24.
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