Rescuing Age-related Proteolysis Deficits with Methylene Blue

Abstract

The average lifespan is constantly increasing with the advent of new medical techniques, and age-related cognitive decline is becoming a prevalent societal issue. Even during healthy aging, humans and rats exhibit progressive deficits in episodic/declarative memory. In laboratory rats, age-related memory impairment can be assessed with trace fear conditioning (TFC). Recent research implicates ubiquitin proteasome system-mediated protein degradation in the synaptic plasticity supporting memory formation and retrieval. In rats, aging leads to decreased basal proteolytic activity in brain structures known to support the acquisition and retrieval of trace fear memories, and our preliminary data suggests activity-dependent proteasome activity declines in a similar fashion. The proposed experiments sought to rescue age-related decreases in plasticity-related protein degradation during memory consolidation via proteasome stimulation with the compound methylthioninium chloride (methylene blue [MB]). Intraperitoneal post-training MB administration at 1, 4, or 16mg/kg did not improve memory performance, chymotrypsin-like, or trypsin-like proteasome activity in young or aged rats in any of the four brain structures examined. Additionally, dietary treatment with MB for four months did not enhance memory, chymotrypsin-like, or trypsin-like proteasome activity in young or aged animals. These results suggest that MB may not be well suited to augment fear learning or to upregulate general proteasome activity. Future work should investigate other means of proteasome stimulation and subsequent rescue of cognitive decline during aging.