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

Alzheimer's 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 Aß 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 Aß42. 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 summary: Chaperone therapy in a mouse model of Alzheimer's disease improves cognition by reducing chronic UPR activity.

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

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.

Acute Sleep Loss Upregulates the Synaptic Scaffolding Protein, Homer1a, in Non-canonical Sleep/Wake Brain Regions, Claustrum, Piriform and Cingulate Cortices.

Homer proteins are a component of the post-synaptic density of neurons that are necessary for the maintenance and consolidation of behavioral state. The dominant negative protein homer1a is rapidly increased by neuronal activity and sleep loss. Homer1a knockout mice with globally absent homer1a have reduced ability to sustain wakefulness during the active period. It is not known whether homer1a is required globally or in very specific brain regions or neurons for its role in maintaining wake. In this study, we examined the expression of homer1a, an immediate early gene involved in intracellular signaling cascades, in mice subjected to extended wakefulness. We found that mice displayed increased expression of homer1a in the claustrum, a brain region thought to be involved in consciousness, as well as the cingulate and piriform cortices compared to non-sleep deprived mice. In situ hybridization (ISH) studies also indicate that homer1a is not induced in the known wake promoting regions with sleep deprivation, but is instead upregulated primarily in the claustrum and piriform cortex. Examination of homer1a expression levels with recovery sleep after sleep deprivation indicate that baseline homer1a expression levels were restored. Further, we have identified that homer1a is upregulated in excitatory neurons of the claustrum suggesting that homer1a promotes wakefulness through activating excitatory neurons. This work identifies regions previously unknown to be involved in sleep regulation that respond to acute sleep deprivation or enhanced waking.

Sleep, Aging, and Cellular Health: Aged-Related Changes in Sleep and Protein Homeostasis Converge in Neurodegenerative Diseases.

Many neurodegenerative diseases manifest in an overall aged population, the pathology of which is hallmarked by abnormal protein aggregation. It is known that across aging, sleep quality becomes less efficient and protein homeostatic regulatory mechanisms deteriorate. There is a known relationship between extended wakefulness and poorly consolidated sleep and an increase in cellular stress. In an aged population, when sleep is chronically poor, and proteostatic regulatory mechanisms are less efficient, the cell is inundated with misfolded proteins and suffers a collapse in homeostasis. In this review article, we explore the interplay between aging, sleep quality, and proteostasis and how these processes are implicated in the development and progression of neurodegenerative diseases like Alzheimer's disease (AD). We also present data suggesting that reducing cellular stress and improving proteostasis and sleep quality could serve as potential therapeutic solutions for the prevention or delay in the progression of these diseases.