Sara Landgren (Institutionen för neurovetenskap och fysiologi); Malin von Otter (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Mona Seibt Palmér (Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin); Caroline Zetterström (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Staffan Nilsson (Institutionen för matematiska vetenskaper, matematisk statistik, Chalmers/GU); Ingmar Skoog (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Deborah Gustafson (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Lennart Minthon (-); Anders Wallin (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Niels Andreasen (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Nenad Bogdanovic (-); J. Marcusson (-); Kaj Blennow (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Henrik Zetterberg (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi); Petronella Kettunen (Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi)

Journal of Neural Transmission, 119 ( 7 ) s. 833-842

0300-9564

Artikel, refereegranskad vetenskaplig

2012

engelska

http://dx.doi.org/10.1007/s00702-012-0823-x

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.

MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Neurovetenskaper

Activity-regulated cytoskeleton-associated protein, Single nucleotide polymorphism, Gene, amyloid-beta-protein, immediate-early gene, cytoskeleton-associated, protein, long-term-memory, synaptic plasticity, messenger-rna, a-beta, cerebrospinal-fluid, cognitive impairment, excitatory synapses, netics

160425

2012-07-12 12:57

2012-08-16 16:07