Biology subjects

Strus, E.

Publications and source records attributed to Strus, E..

3 recordsLinked to original sources

bioRxiv2026

Chronic short sleep in early life accelerates cognitive decline via disrupted proteostasis

Chronic short sleep (CSS) is an emerging public health issue that frequently begins in adolescence and is common among healthcare professionals and others engaged in shift work. Epidemiological studies associate CSS and sleep disruption with metabolic disorders, cardiovascular disease, cognitive decline, and heightened Alzheimers disease risk. Building on our prior findings that sleep deprivation perturbs proteostasis and activates endoplasmic reticulum (ER) stress pathways, we investigated the long-term consequences of CSS in young adult wild-type mice over the course of one year. Mice exposed to CSS displayed impaired cognition in hippocampal dependent tasks by 28 weeks of age, indicating emerging memory deficits. At the molecular level, CSS disrupted hippocampal proteostasis--particularly protein folding processes--and triggered ER stress and activation of the unfolded protein response (UPR). Importantly, disrupted proteostasis preceded the behavioral decline, with diminution of the key chaperone and UPR regulator BiP occurring at 20-22 weeks of age. CSS also increased markers of cellular stress and neuroinflammation while reducing the expression of proteins associated with memory function. Age also seemed to be a cellular stressor, causing a longitudinal increase in UPR, ISR, and neuroinflammation markers. Together, these results indicate that both chronic short sleep and age compromise proteostasis and promote neuroinflammation, contributing to progressive cognitive dysfunction.

neuroscience↗

bioRxiv2026

Hippocampal BiP Overexpression Rescues Cognitive Performance and Increases REM theta in 3xTg Mouse Model of Alzheimer's Disease

The accumulation of A{beta} plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimers disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, A{beta} and A{beta}42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD.

neuroscience↗

bioRxiv2023

Early and late chaperone intervention therapy boosts XBP1s and ADAM10, restores proteostasis, and rescues learning in Alzheimer's Disease mice

Alzheimers disease (AD) is a debilitating neurodegenerative disorder that is pervasive among the aging population. Two distinct phenotypes of AD are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant A{beta} production. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock-in mouse model of AD and several protein chaperone supplementation paradigms, including a late-stage intervention. We show that supplementing protein chaperones systemically and locally in the hippocampus reduces PERK signaling and increases XBP1s, which is associated with increased ADAM10 and decreased A{beta}42. Importantly, chaperone treatment improves cognition which is correlated with increased CREB phosphorylation and BDNF. Together, this data suggests that chaperone treatment restores proteostasis in a mouse model of AD and that this restoration is associated with improved cognition and reduced pathology. One-sentence summaryChaperone therapy in a mouse model of Alzheimers disease improves cognition by reducing chronic UPR activity

neuroscience↗