A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease
Artikel i vetenskaplig tidskrift, 2012

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.

cerebrospinal-fluid

long-term-memory

cognitive impairment

messenger-rna

immediate-early gene

a-beta

synaptic plasticity

amyloid-beta-protein

excitatory synapses

cytoskeleton-associated protein

Författare

Sara Landgren

Sahlgrenska akademin

Malin von Otter

Sahlgrenska akademin

Mona Seibt Palmer

Sahlgrenska akademin

Caroline Zetterstrom

Sahlgrenska akademin

Staffan Nilsson

Chalmers, Matematiska vetenskaper, matematisk statistik

Göteborgs universitet

Ingmar Skoog

Sahlgrenska akademin

Deborah Gustafson

Sahlgrenska akademin

L. Minthon

Lunds universitet

Anders Wallin

Sahlgrenska akademin

Niels Andreasen

Karolinska Institutet

Nenad Bogdanovic

Karolinska Institutet

Jan Marcusson

Linköpings universitet

Kaj Blennow

Sahlgrenska akademin

Henrik Zetterberg

Sahlgrenska akademin

UCL Institute of Neurology

Petronella Kettunen

Sahlgrenska akademin

Journal of Neural Transmission

0300-9564 (ISSN)

Vol. 119 7 833-842

Ämneskategorier

Neurologi

DOI

10.1007/s00702-012-0823-x

Mer information

Senast uppdaterat

2018-03-23