Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice

Abstract

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 p‐CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone‐treated aged mice. 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. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.

Amide Proton Transfer-Weighted Imaging Detects Hippocampal Proteostasis Disturbance Induced by Sleep Deprivation at 7.0 T MRI

“…As a major regulator in proteostasis disturbance signaling pathways, GRP78 plays a key role in ER stress . Recent study showed that supplementing the level of GRP78 can reduce ER stress and improve cognition in aging mice . These findings highlight the relationship between GRP78 and ER stress.…”

Hippocampal Endoplasmic Reticulum Stress Hastens Motor and Cognitive Decline in Adult Male Rats Sustainedly Exposed to High-Sucrose Diet

“…Although the underlying signaling pathways are still elusive, endoplasmic reticulum (ER) stress has emerged as a potential linking mechanism. This assumption is supported by recent demonstrations that cognitive function is impaired by ER stressors like deltamethrin [ 13 ] and sevoflurane [ 14 ] but improved by the administration of 4-phenyl butyrate, a chemical chaperone, to aged rats [ 15 ].…”

Ketogenic diet administration later in life improves memory and regulates the synaptic cortical proteome through the cAMP/PKA signaling pathway in aging mice

“…Interestingly, therapies that promote the activation of mechanisms involved in protein folding enhance cognitive function in aging mice (Bobkova et al 2015). Recently, Hafycz and cols, administrated a chemical chaperone 4-phenyl butyrate into aged mice and observed improved learning through increased p-CREB, a key protein involved in memory consolidation (Hafycz, Strus, and Naidoo 2022). In this work, we evaluated the changes in the cortical proteome of aged mice after a long-term administration of a cyclic KD, as optimized in (Newman et al 2017).…”