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A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease

Landgren, Sara; von Otter, Malin; Palmer, Mona Seibt; Zetterstrom, Caroline; Nilsson, Staffan; Skoog, Ingmar; Gustafson, Deborah R.; Minthon, Lennart LU ; Wallin, Anders and Andreasen, Niels, et al. (2012) In Journal of Neural Transmission 119(7). p.833-842
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we... (More)
Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed. (Less)
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published
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keywords
Activity-regulated cytoskeleton-associated protein, Single nucleotide, polymorphism, Gene association, Alzheimer's disease, Memory, Immediate-early gene
in
Journal of Neural Transmission
volume
119
issue
7
pages
833 - 842
publisher
Springer
external identifiers
  • wos:000305525800013
  • scopus:84863446685
ISSN
0300-9564
DOI
10.1007/s00702-012-0823-x
language
English
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yes
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fb1f997d-e45c-4587-8546-bc6054e4bb04 (old id 2883926)
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2012-08-01 09:41:17
date last changed
2017-10-01 04:10:13
@article{fb1f997d-e45c-4587-8546-bc6054e4bb04,
  abstract     = {Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.},
  author       = {Landgren, Sara and von Otter, Malin and Palmer, Mona Seibt and Zetterstrom, Caroline and Nilsson, Staffan and Skoog, Ingmar and Gustafson, Deborah R. and Minthon, Lennart and Wallin, Anders and Andreasen, Niels and Bogdanovic, Nenad and Marcusson, Jan and Blennow, Kaj and Zetterberg, Henrik and Kettunen, Petronella},
  issn         = {0300-9564},
  keyword      = {Activity-regulated cytoskeleton-associated protein,Single nucleotide,polymorphism,Gene association,Alzheimer's disease,Memory,Immediate-early gene},
  language     = {eng},
  number       = {7},
  pages        = {833--842},
  publisher    = {Springer},
  series       = {Journal of Neural Transmission},
  title        = {A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease},
  url          = {http://dx.doi.org/10.1007/s00702-012-0823-x},
  volume       = {119},
  year         = {2012},
}