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

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) 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 Aβ 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 Aβ(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.

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

“…A landmark study published in 2011 showed that Arc protein is required for the formation of amyloid (Aβ) plaques 80 . Moreover, Arc protein levels are aberrantly regulated in the hippocampus of AD patients 209 , and are locally upregulated around amyloid plaques 210 , whereas a polymorphism in the Arc gene confers a decreased likelihood of developing AD 211 . It has been shown that spatial memory impairment is associated with dysfunctional Arc expression in the hippocampus of an AD mouse model 212 .…”

Roles for Arc in metabotropic glutamate receptor-dependent LTD and synapse elimination: Implications in health and disease

“…Due to the strong links of Arc with learning and memory in healthy animals, perhaps is it not surprising that alterations in Arc and Arc-dependent synaptic plasticity are associated neuropsychiatric diseases, especially those accompanied by cognitive dysfunction. Although mutations in Arc itself are not prevalent in these diseases, dysregulation of Arc mRNA, protein levels or mutations in regulators or interacting proteins of Arc are linked with intellectual disability, autism [13, 29, 31, 104–108], Alzheimer’s disease [109–111], depression [60] and schizophrenia [112–117]. As discussed below, alterations in mGluR-LTD and synapse elimination are associated with these diseases, and some evidence suggests this is mediated by dysregulation of Arc.…”

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

“…These novel findings emphasize the need to understand the physiological function of the AIS, and the implications of AIS disorder and dysfunction. Recent advances in human genetic research are essential for the advancement of psychiatric research, but may not be sufficient to understand every aspect of complex disease spectrums (19, 20). New methods to integrate gene activity and proteomic datasets, derived from biobank samples with associated clinical metadata, promise to provide the field with powerful tools to more precisely define the molecular phenotypes of psychiatric illnesses (21).…”