Using Chaperones to Reduce Endoplasmic Reticulum Stress Improves Sleep and Cognition in Aged Mice

4-phenyl butyrate can be delivered orally, and once inside cells it mimics some of the natural chaperone molecules that aid in protein folding in the endoplasmic reticulum. Improved the quality and pace of protein folding leads to better cell function, particularly given that rising levels of endoplasmic reticulum stress and impairment in the compensatory unfolded protein response are observed in aged tissues. Addressing this issue can improve the state of tissue function in aged animals, at least to some degree, as demonstrated in the research results noted here.

As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient.

It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice.

Chaperone treatment increased phosphorylated CREB (p-CREB), which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Further, hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging.


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