New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease

[EN] We have previously proposed a radical change in the current strategy to clear pathogenic proteins from the central nervous system (CNS) based on the cerebrospinal fluid (CSF)-sink therapeutic strategy, whereby pathogenic proteins can be removed directly from the CNS via CSF. To this aim, we designed and manufactured an implantable device for selective and continuous apheresis of CSF enabling, in combination with anti-amyloid-beta (Aβ) monoclonal antibodies (mAb), the clearance of Aβ from the CSF. Here, we provide the first proof of concept in the APP/PS1 mouse model of Alzheimer’s disease (AD). Devices were implanted in twenty-four mice (seventeen APP/PS1 and seven Wt) with low rates of complications. We confirmed that the apheresis module is permeable to the Aβ peptide and impermeable to mAb. Moreover, our results showed that continuous clearance of soluble Aβ from the CSF for a few weeks decreases cortical Aβ plaques. Thus, we conclude that this intervention is feasible and may provide important advantages in terms of safety and efficacy.This work was supported by the Instituto de Salud Carlos III, under Grant DTS19-00071 to M.M.-G. and by the Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología (FICYT), under Grant AYUD/2021/57540, to C.T.-Z

Next‐generation sequencing reveals that miR‐16‐5p, miR‐19a‐3p, miR‐451a, and miR‐25‐3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes

A sedentary lifestyle and Olympic participation are contrary risk factors for global mortality and incidence of cancer and cardiovascular disease. Extracellular vesicle miRNAs have been described to respond to exercise. No molecular characterization of young male sedentary people versus athletes is available; so, our aim was to identify the extracellular vesicle miRNA profile of chronically trained young endurance and resistance male athletes compared to their sedentary counterparts. A descriptive case–control design was used with 16 sedentary young men, 16 Olympic male endurance athletes, and 16 Olympic male resistance athletes. Next‐generation sequencing and RT‐qPCR and external and internal validation were performed in order to analyze extracellular vesicle miRNA profiles. Endurance and resistance athletes had significant lower levels of miR‐16‐5p, miR‐19a‐3p, and miR‐451a compared to sedentary people. Taking all together, exercise‐trained miRNA profile in extracellular vesicles provides a differential signature of athletes irrespective of the type of exercise compared to sedentary people. Besides, miR‐25‐3p levels were specifically lower in endurance athletes which defines its role as a specific responder in this type of athletes. In silico analysis of this profile suggests a role in adaptive energy metabolism in this context that needs to be experimentally validated. Therefore, this study provides for the first time basal levels of circulating miRNA in extracellular vesicles emerge as relevant players in intertissue communication in response to chronic exercise exposure in young elite male athletes

Physical exercise shapes the mouse brain epigenome

[Objective]: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice.[Methods]: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function.[Results]: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions.[Conclusions]: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research.This work was supported by the Spanish Association Against Cancer (PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) co-funding 2018-2022/FEDER (IDI/2018/146 to M.F.F.), the Fundación General CSIC (0348_CIE_6_E to M.F.F.), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527 to M.F.F and A.F.F.), the MINECO (DEP2015-69980-P to B.F.G.), and the Fundación Tatiana Pérez de Guzmán el Bueno (“Ayudas a Proyectos de Investigación en Neurociencia-2020” to C.T.Z and E.I.G.). R.G.U. is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). J.R.T. is supported by a Juan de la Cierva fellowship from the Spanish Ministry of Science and Innovation MCIN/AEI /10.13039/501100011033 (IJC2018-036825-I). R.F.P. is supported by the Severo Ochoa program (BP17-114). P.P.H. is supported by Ayudas para la realización de Tesis Doctorales. Modalidad A fellowship from the University of Oviedo (PAPI-20-PF-19). We also acknowledge support from the IUOPA-ISPA-FINBA (the IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain).Peer reviewe

Supplementary material Next-generation sequencing reveals that miR-16-5p, miR-19a-3p, miR-451a and miR-25-3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes.

<p>A sedentary lifestyle is a leading risk factor for global mortality. No objective molecular biomarker of sedentarism is available. Extracellular vesicles miRNAs have been described to respond to exercise. Our aim was to identify the extracellular vesicle miRNA profile of chronically trained young male athletes, endurance and resistance, compared to their sedentary counterparts. A descriptive case-control design with 16 sedentary young men, 16 Olympic male endurance athletes and 16 Olympic male resistance athletes. Next Generation Sequencing and RT-qPCR, external and internal validation, were performed in order to analysed extracellular vesicle miRNA profiles. miR-16-5p, miR-19a-3p and miR-451a were significantly upregulated in SED compared to END and RES. Besides, miR-25-3p was specifically down-regulated in END compared to SED. Extracellular vesicle miR-16-5p, miR-19a-3p, miR-451a provide an objective signature of sedentarism irrespective of the type of exercise and miR-25-3p as a specific responder to endurance training. Therefore, this study provides for the first time an objective measure to categorise individuals as sedentary or trained in young male population and moreover, it highlights a common epigenetic modulation between models of training.</p&gt

Supplementary material Next-generation sequencing reveals that miR-16-5p, miR-19a-3p, miR-451a and miR-25-3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes.

<p>A sedentary lifestyle is a leading risk factor for global mortality. No objective molecular biomarker of sedentarism is available. Extracellular vesicles miRNAs have been described to respond to exercise. Our aim was to identify the extracellular vesicle miRNA profile of chronically trained young male athletes, endurance and resistance, compared to their sedentary counterparts. A descriptive case-control design with 16 sedentary young men, 16 Olympic male endurance athletes and 16 Olympic male resistance athletes. Next Generation Sequencing and RT-qPCR, external and internal validation, were performed in order to analysed extracellular vesicle miRNA profiles. miR-16-5p, miR-19a-3p and miR-451a were significantly upregulated in SED compared to END and RES. Besides, miR-25-3p was specifically down-regulated in END compared to SED. Extracellular vesicle miR-16-5p, miR-19a-3p, miR-451a provide an objective signature of sedentarism irrespective of the type of exercise and miR-25-3p as a specific responder to endurance training. Therefore, this study provides for the first time an objective measure to categorise individuals as sedentary or trained in young male population and moreover, it highlights a common epigenetic modulation between models of training.</p&gt

Dynamics of Gut Microbiota and Short-Chain Fatty Acids during a Cycling Grand Tour Are Related to Exercise Performance and Modulated by Dietary Intake

Background: Regular exercise has been described to modify both the diversity and the relative abundance of certain bacterial taxa. To our knowledge, the effect of a cycling stage race, which entails extreme physiological and metabolic demands, on the gut microbiota composition and its metabolic activity has not been analysed. Objective: The aim of this cohort study was to analyse the dynamics of faecal microbiota composition and short-chain fatty acids (SCFAs) content of professional cyclists over a Grand Tour and their relationship with performance and dietary intake. Methods: 16 professional cyclists competing in La Vuelta 2019 were recruited. Faecal samples were collected at four time points: the day before the first stage (A); after 9 stages (B); after 15 stages (C); and on the last stage (D). Faecal microbiota populations and SCFA content were analysed using 16S rRNA sequencing and gas chromatography, respectively. A principal component analysis (PCA) followed by Generalised Estimating Equation (GEE) models were carried out to explore the dynamics of microbiota and SCFAs and their relationship with performance. Results: Bifidobacteriaceae, Coriobacteriaceae, Erysipelotrichaceae, and Sutterellaceae dynamics showed a strong final performance predictive value (r = 0.83, ranking, and r = 0.81, accumulated time). Positive correlations were observed between Coriobacteriaceae with acetate (r = 0.530) and isovalerate (r = 0.664) and between Bifidobacteriaceae with isobutyrate (r = 0.682). No relationship was observed between SCFAs and performance. The abundance of Erysipelotrichaceae at the beginning of La Vuelta was directly related to the previous intake of complex-carbohydrate-rich foods (r = 0.956), while during the competition, the abundance of Bifidobacteriaceae was negatively affected by the intake of simple carbohydrates from supplements (r = −0.650). Conclusions: An ecological perspective represents more realistically the relationship between gut microbiota composition and performance compared to single-taxon approaches. The composition and periodisation of diet and supplementation during a Grand Tour, particularly carbohydrates, could be designed to modulate gut microbiota composition to allow better performance

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Abstract Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline