Academy

CREB Signaling and Memory in Aging

Introduction

The cAMP response element–binding protein (CREB) is a pivotal transcription factor that regulates the expression of genes required for neuronal plasticity and memory consolidation across species. Understanding CREB signaling provides insight into how memory is formed, maintained, and how it declines during aging.

What Is CREB?

• CREB is a protein that binds to specific DNA sequences called cAMP response elements (CRE) in the promoters of target genes.
• Upon activation by phosphorylation (commonly via protein kinase A, CaMKII, or MAPK pathways), CREB recruits coactivators like CBP/p300 to drive gene transcription.
• CREB plays roles in synaptic strengthening, new synapse formation, and long-term potentiation (LTP), all key processes for memory formation.

CREB in Memory Formation

1. Learning Trigger: An initial stimulus activates signaling cascades (e.g., calcium influx, second messengers) that converge on CREB kinases.
2. CREB Activation: Kinases phosphorylate CREB at serine 133, enabling it to bind CRE sites.
3. Gene Transcription: Phospho-CREB recruits coactivators, initiating transcription of plasticity-related genes (e.g., BDNF, c-Fos, Arc).
4. Synaptic Changes: Gene products strengthen synaptic connections and support synapse growth, stabilizing memory traces.

Age-Related CREB Decline

With aging, basal CREB expression and phosphorylation levels often decrease, leading to reduced plasticity gene expression and impaired memory. Strategies to maintain or enhance CREB activity in neurons have shown promise in reversing cognitive deficits in aged models.

Non-Neuronal Regulation of CREB

• Recent findings in C. elegans demonstrate that peripheral tissues, such as the hypodermis (analogous to liver/skin), can modulate neuronal CREB levels via systemic signaling pathways.
• Reduction of the insulin/IGF-1 receptor (DAF-2) in hypodermal cells triggers secretion of the Notch ligand OSM-11, which non-autonomously activates Notch receptors in neurons.
• This body-to-brain pathway culminates in CREB upregulation and enhanced memory retention, even during aging.

Implications for Longevity and Cognitive Health

Targeting peripheral regulators of CREB may offer a dual benefit: improving metabolic health and preserving cognitive function. Therapies aimed at modulating insulin and Notch pathways outside the brain could help maintain memory capacity with age.

Conclusion

CREB remains a master regulator of memory, and its activity can be influenced by both neuronal and non-neuronal signals. Integrating our understanding of CREB’s role in synaptic plasticity with systemic endocrine pathways provides a comprehensive framework for developing interventions to combat cognitive aging.