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

Abstract

The immediate-early gene Arc is a master regulator of synaptic function and a critical determinant of memory consolidation. Arc protein is localized to excitatory synapses, where it controls AMPA receptor endocytosis, and to the nucleus, where it associates with Tip60, a subunit of a chromatin modifying complex. Here we show that Arc interacts with dynamic chromatin loops and associates with histone markers for active enhancers and transcription in cultured hippocampal neurons. When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes. Many gene families were affected by the absence of Arc, most notably those associated with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Interestingly, about 100 genes whose activitydependent expression level depends on Arc are associated with the pathophysiology of Alzheimer's disease, suggesting a critical role for Arc in the development of neurodegenerative disorders. When endogenous Arc expression was induced in a non-neuronal cell line (HEK293T), the transcription of many neuronal genes was increased, suggesting Arc can control expression in the absence of activated signaling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and a significant factor underlying the pathophysiology Alzheimer's disease.

DNA methylation in the pathology of Alzheimer's disease: from gene to cognition

“…The absence of Arc expression was associated with the downregulation of genes highly implicated in memory, such as brain-derived neurotrophic factor (Bdnf) and calcium/calmodulin-dependent protein kinase IV (Camkiv); genes associated with tau protein pathology, such as neuronal PAS domain protein 4 (Npas4) and dual specificity tyrosine phosphorylation-regulated kinase 2 (Dyrk2); and genes alleviating Aβ pathology, such as integral membrane protein 2B (Itm2b) and LDL receptorrelated protein 1 (Lrp1). 91 These findings further support the essential roles of Arc, as well as consequences of a dysregulated genomic network in AD. In spite of its apparent importance, studies of Arc methylation in AD are surprisingly scarce.…”

“…Indeed, RNA sequencing combined with gene ontology revealed that Arc has an inhibitory effect on Aβ-related processes and NFTs. 91 Besides, Arc is also thought to have significant effects on the expression of AD susceptibility genes. The absence of Arc expression was associated with the downregulation of genes highly implicated in memory, such as brain-derived neurotrophic factor (Bdnf) and calcium/calmodulin-dependent protein kinase IV (Camkiv); genes associated with tau protein pathology, such as neuronal PAS domain protein 4 (Npas4) and dual specificity tyrosine phosphorylation-regulated kinase 2 (Dyrk2); and genes alleviating Aβ pathology, such as integral membrane protein 2B (Itm2b) and LDL receptorrelated protein 1 (Lrp1).…”

Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimer’s Disease

“…8A). 4-AP is an A-type potassium channel blocker that can induce epileptiform activity in the rat hippocampus 32 . In our assay, we observed that the frequency of spikes was increased about 2-fold by addition of 10 μM 4-AP in both i-Control and AD organoids, but there was no significant difference between them before or after drug treatment (Fig.…”

The Potential Mechanisms of the Neuroprotective Actions of Oil Palm Phenolics: Implications for Neurodegenerative Diseases

“…Another gene up-regulated by OPP is Arc (activity-regulated cytoskeletal-associated protein), which is a master regulator of synaptic function that has a critical role in late-phase of long-term potentiation and memory consolidation [122]. The expression of Fos (Finkel-Biskis-Jinkins osteosarcoma) and Dlgh4 (discs large homolog 4) genes, which are the markers for neuronal and post-synaptic activities, are also up-regulated by OPP.…”