2025-10-22 バージニア工科大学 (Virginia Tech)
<関連情報>
- https://news.vt.edu/articles/2025/10/cals-jarome-improving-memory.html
- https://www.ibroneuroscience.org/article/S0306-4522(25)00714-6/abstract
- https://www.sciencedirect.com/science/article/pii/S0361923025003211
海馬と扁桃体におけるプロテアソーム非依存性K63ポリユビキチン化の加齢による調節異常 Age-related dysregulation of proteasome-independent K63 polyubiquitination in the hippocampus and amygdala
Yeeun Bae ∙ Harshini Venkat ∙ Natalie Preveza ∙ W.Keith Ray ∙ Richard F. Helm ∙ Timothy J. Jarome
Neuroscience Published:June 14, 2025
DOI:https://doi.org/10.1016/j.neuroscience.2025.06.032
Highlight
- Aging increases K63 levels in the hippocampus but reduces it in the amygdala.
- Reducing K63 levels in the aged hippocampus and amygdala improves memory.
- Reducing K63 levels in the middle-aged hippocampus and amygdala has no effect on memory.
Abstract
Cognitive decline with aging is a complex process involving multiple brain regions and molecular mechanisms. While the role of the canonical protein degradation function of the ubiquitin–proteasome system (UPS) has been well studied in the context of aging and age-associated memory loss, the non-proteolytic functions of ubiquitin activity remain poorly understood. Here, we investigated the role of lysine-63 (K63) polyubiquitination, the most abundant form of proteasome-independent ubiquitination, in aged rats, focusing on the hippocampus and amygdala, two brain regions reported to have cellular and molecular alterations with age that are associated with age-related memory loss. Using an unbiased proteomic approach, we observed a significant increase of K63 polyubiquitination in the hippocampus across the lifespan. Reducing K63 polyubiquitination in the hippocampus of aged male rats using the CRISPR-dCas13 RNA editing system enhanced contextual fear memory, while similar manipulations in middle-aged rats, which typically have normal memory, had no effect, emphasizing the age-dependent role of K63 polyubiquitination in memory formation. Conversely, the amygdala showed a consistent reduction of K63 polyubiquitination protein targets across the lifespan, and further reductions of K63 polyubiquitination improved memory retention in aged, but not middle-aged, male rats. Together, our findings reveal the dynamic and region-specific functions of K63 polyubiquitination in the brain aging process, providing novel insights into its contribution to age-associated memory decline.
男性海馬におけるIgf2のDNAメチル化の増加は、シナプス可塑性と記憶における加齢に伴う障害を制御する Increased DNA methylation of Igf2 in the male hippocampus regulates age-related deficits in synaptic plasticity and memory
Shannon Kincaid, Courtney P. Stickling, Kayla Farrell, Yeeun Bae, Morgan B. Patrick, Gitali Bhanot, Adam Cummings, Jennifer Abraham, Abby Alisesky, Nicole Ferrara, J. Amiel Rosenkranz, Timothy J. Jarome
Brain Research Bulletin Available online: 11 August 2025
DOI:https://doi.org/10.1016/j.brainresbull.2025.111509
Highlights
- Igf2 methylation increases and gene expression decreases in the male aged hippocampus.
- Increasing DNA 5-hmC in the promoter of Igf2 improves memory and synaptic plasticity in the aged hippocampus.
- Increasing DNA 5-hmC in the promoter of Igf2 has no effect on memory and synaptic plasticity in the middle-aged hippocampus.
Abstract
The aging process is characterized by a general decline in cognitive abilities, which affects nearly 33 % of U.S. adults over the age of 70 and is a risk factor for the development of dementia and Alzheimer’s disease. Numerous studies have reported increased neuroinflammation and impaired synaptic plasticity and memory with age in the hippocampus, a major brain region involved in the formation and storage of most memories. However, much remains unknown about the mechanisms that contribute to age-related deficits in synaptic plasticity and memory. The Insulin-like growth factor 2 (Igf2) is a genomic imprinted gene that is expressed from a single allele in all species. Though IGF2 has been shown to be important in development, synaptic plasticity, and memory formation in the hippocampus and administration of IGF2 can improve memory late in life, whether changes in regulation of this gene contribute to age-related memory decline have yet to be explored. Here, we show that aged (24 months) male rats have increased CpG-site specific promoter methylation and reduced expression of Igf2 in the hippocampus relative to young adult (3 months) and middle-aged (12 months) rats. Importantly, CRISPR-dCas9 mediated increase of DNA 5-hydroxymethylation, an active transcriptional mark, of the Igf2 promoter in the hippocampus improved memory and long-term potentiation in aged, but not middle-aged, rats. These data indicate that increased DNA methylation of Igf2 in the hippocampus contributes to age-related deficits in synaptic plasticity and memory.
