'Arc'-hitecture of normal cognitive aging

Abstract

Arc is an effector immediate-early gene that is critical for forming long-term memories. Since its discovery 25 years ago, it has repeatedly surprised us with a number of intriguing properties, including the transport of its mRNA to recently-activated synapses, its master role in bidirectionally regulating synaptic strength, its evolutionary retroviral origins, its ability to mediate intercellular transfer between neurons via extracellular vesicles (EVs), and its exceptional regulation-both temporally and spatially. The current review discusses how Arc has been used as a tool to identify the neural networks involved in cognitive aging and how Arc itself may contribute to cognitive outcome in aging. In addition, we raise several outstanding questions, including whether Arc-containing EVs in peripheral blood might provide a noninvasive biomarker for memory-related synaptic failure in aging, and whether rectifying Arc dysregulation is likely to be an effective strategy for bending the arc of aging toward successful cognitive outcomes.

Keywords: Arc; Immediate early gene; Memory; Normal cognitive aging; Plasticity.

Figure 1.. Overview of the ‘Arc’-hitecture of normal cognitive aging.

The adaptive capacity of the brain over the lifespan depends on synaptic plasticity—a process where the immediate early gene product Arc plays a critical role. Many studies have examined Arc in the context of aging. While some have identified differences associated with chronological age (top panel, gray), others have utilized animal models that recapitulate the age-related increase in interindividual variability in cognitive performance observed in humans—from aged individuals that retain young-like memory capacity (top panel, green), to aged rats displaying substantial impairment (top panel, purple). The bottom panels use the same color scheme—gray, green, and purple—to highlight findings specific to either chronological age, aging with relatively spared memory, and aging with impaired memory, respectively. Yellow boxes highlight outstanding questions. A. Epigenetic regulation of ARC transcription is disrupted in cognitive aging. Aged rats with spatial memory impairment display elevated methylation levels at its promoter and an enrichment of the H3K9Me2 transcriptional repression histone mark, compared to young rats and aged rats with intact memory. Aged impaired and young rats show enrichment of the synaptic activity histone mark H3K9AcS10p compared to aged unimpaired rats. B. Constitutive Arc mRNA transcription is elevated in aged animals with cognitive impairment, while activity-dependent transcription is blunted. Available evidence indicates that Arc mRNA turnover is unaltered in aging, while the fidelity of Arc mRNA transport to recently activated dendritic spines remains to be investigated in the aged brain. C. Constitutively elevated Arc protein levels, together with blunted activity-dependent Arc translation and reduced proteasome-dependent degradation, have been reported in aged animals with cognitive impairment. Whether or not Arc interaction partners shift with age, or whether Arc post-translational modifications remain intact in normal cognitive has not been investigated. D. Studies aiming to identify age-related changes in Arc oligomerization and viral-like capsid function may provide valuable insight into the mechanisms of memory and how they diverge during the lifespan to influence cognitive outcome. E. Assessing experience-induced Arc transcription has provided a window on the spatial distribution and temporal dynamics of aberrant neural networks and regional vulnerability in cognitive aging. Current literature using Arc imaging as a proxy for neuronal activity has identified relevant brain regions and circuits involved in memory formation and storage, including the hippocampus, parahippocampal cortices, and prefrontal cortex. Overall, activity-induced Arc expression seems to be reduced in aging. Still, unique expression patterns can be observed in cognitively impaired animals when specific subregions and circuits are examined, and when the behavioral assessment used to induce activity is configured to involve sufficient cognitive demand.