Small molecule cognitive enhancer reverses age-related memory decline in mice
Karen KrukowskiAmber NolanElma S. FriasMorgane BooneGonzalo UretaKatherine GrueMaria Serena PaladiniEdward ElizarrarasLuz DelgadoSebastián BernalesPeter WalterSusanna Rosi
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With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.Keywords:
Cognitive Decline
Integrated stress response
Abstract Objectives Subjective cognitive decline (SCD) is a known risk factor for Alzheimer’s disease. However, little research has examined whether healthy older adults with SCD (SCD+) exhibit lower cognition and increased rates of cognitive decline compared to those without SCD (SCD−). The goal of this study was to examine if cognitive change over a 15-year period differs between SCD+ and SCD−. Method 3,019 cognitively normal older adults (831 SCD+) from 3 Rush Alzheimer’s Disease Center cohort studies were followed annually for up to a maximum of 15 years. Due to attrition, the average follow-up time was 5.7 years. Cognition was measured using z-scores of global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory. Linear mixed-effects models investigated whether SCD was associated with cognitive change. Results Both baseline cognition and cognitive change over time differed between SCD+ and SCD−. People with SCD+ exhibited lower baseline scores and a steeper decline in global cognition, episodic memory, semantic memory, and perceptual speed. People with SCD+ did not differ from SCD− in baseline visuospatial ability or working memory but exhibited increased change over time in those two domains compared to SCD−. Discussion The observed results reveal that older adults with SCD+ have lower baseline cognition and steeper declines in cognition over time compared to SCD−. Older adults with SCD may be aware of subtle cognitive declines that occur over time in global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory compared to those without SCD.
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Gene expression is determined by genomic elements called enhancers, which contain short motifs bound by different transcription factors (TFs). However, how enhancer sequences and TF motifs relate to enhancer activity is unknown, and general sequence requirements for enhancers or comprehensive sets of important enhancer sequence elements have remained elusive. Here, we computationally dissect thousands of functional enhancer sequences from three different Drosophila cell lines. We find that the enhancers display distinct cis -regulatory sequence signatures, which are predictive of the enhancers’ cell type-specific or broad activities. These signatures contain transcription factor motifs and a novel class of enhancer sequence elements, dinucleotide repeat motifs (DRMs). DRMs are highly enriched in enhancers, particularly in enhancers that are broadly active across different cell types. We experimentally validate the importance of the identified TF motifs and DRMs for enhancer function and show that they can be sufficient to create an active enhancer de novo from a nonfunctional sequence. The function of DRMs as a novel class of general enhancer features that are also enriched in human regulatory regions might explain their implication in several diseases and provides important insights into gene regulation.
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Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Here, we investigate the 3D conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues. 61% of developmental enhancers bypass their neighboring genes, which are often marked by promoter CpG methylation. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are moderately but consistently increased upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, these invariant interactions form in the absence of the enhancer and are likely mediated by adjacent CTCF binding. Our results highlight the general significance of enhancer-promoter physical proximity for developmental gene activation in mammals.
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Enhancer elements regulate the tissue- and developmental-stage-specific expression of genes. Recent estimates suggest that there are more than 50,000 enhancers in mammalian cells. At least a subset of enhancers has been shown to recruit RNA polymerase II transcription complexes and to generate enhancer transcripts. Here, we provide an overview of enhancer function and discuss how transcription of enhancers or enhancer-generated transcripts could contribute to the regulation of gene expression during development and differentiation.
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This paper reviews different methodological approaches taken to examine terminal decline in cognitive function, and presents new findings from the Bronx Aging Study (BAS). Numerous approaches have been taken to assess mortality effects on cognition: comparing survivors and decedents level and rate of change in cognition, and identifying individual differences in cognition associated with time-to-death. However, few studies have actually modeled within-person change in cognition as a function of time-to-death. Using linear mixed models with a change point, intraindividual change in episodic memory was modeled as a function of both age and time-to-death. A dramatic increase in the rate of decline was identified at 8.4 years prior to death, providing clear evidence of a terminal-decline phase that is much longer than previously estimated. These results emphasize the importance of modeling the time course and effects of terminal cognitive decline for understanding cognitive change in aging adults.
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With dementia incidence projected to escalate significantly within the next 25 years, the United Nations declared 2021-2030 the Decade of Healthy Ageing, emphasising cognition as a crucial element. As a leading discipline in cognition and ageing research, psychology is well-equipped to offer insights for translational research, clinical practice, and policy-making. In this comprehensive review, we discuss the current state of knowledge on age-related changes in cognition and psychological health. We discuss cognitive changes during ageing, including (a) heterogeneity in the rate, trajectory, and characteristics of decline experienced by older adults, (b) the role of cognitive reserve in age-related cognitive decline, and (c) the potential for cognitive training to slow this decline. We also examine ageing and cognition through multiple theoretical perspectives. We highlight critical unresolved issues, such as the disparate implications of subjective versus objective measures of cognitive decline and the insufficient evaluation of cognitive training programs. We suggest future research directions, and emphasise interdisciplinary collaboration to create a more comprehensive understanding of the factors that modulate cognitive ageing.
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Abstract There is variability in cognitive aging between individuals. This study aimed to investigate cognitive aging trajectories, the associated modifiable factors, and the association of these trajectories with dementia. Community-dwelling older adults (n=19,114) without dementia or major cognitive impairment at inclusion were followed for up to 7 years, with regular standardized cognitive assessments. Group-based (multi-) trajectory modeling identified distinct cognitive trajectories. Structural equation modeling (n=16,018) was used to analyze the associated predictors. Four to seven trajectories were identified per cognitive domain, with generally stable trajectories. Improvement in verbal fluency and minor psychomotor slowing were common. Substantial decline in global cognition and episodic memory were observed in a small proportion of individuals. The highest proportions of dementia cases were in trajectories with major decline in global cognition (56.9%) and memory (33.2%). A number of sociodemographic characteristics, health behaviors and chronic conditions were either directly or indirectly associated with cognitive change in older adults. This study found that some individuals appear resilient to cognitive decline even with advancing age, and that factors that promote healthy cognitive aging are not simply the absence of factors which confer risk for decline.
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Gene transcription can be regulated by promoter competition when multiple promoters are available for a single enhancer. The converse, however, is largely undescribed. Here we report an occurrence of several enhancers competing for one promoter (enhancer interference) and propose its underlying mechanism. The promoter targeting sequence from the Abdominal-B locus of the Drosophila bithorax complex overcomes the enhancer-blocking activity of insulators in transgenic embryos. It may facilitate the long-range enhancer–promoter communication in Abdominal-B by bypassing insulator elements such as Frontabdominal-7 and Frontabdominal-8 . In transgenic embryos, the anti-insulator activity allowed both an insulator-blocked enhancer and a nonblocked enhancer to contact the same promoter. We found that these two enhancers exhibited mutual inhibition or mutual exclusion in cells where both are transcriptionally active. This enhancer interference occurred at the level of enhancer–promoter communication. It occurred only between enhancers on opposite sides of an insulator and depended on enhancer activity. We hypothesize that enhancer interference limits the interaction of the Abdominal-B promoter to the enhancer(s) from only one regulatory domain in a specific abdominal segment.
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