Hippocampal rejuvenation by a single intracerebral injection of one-carbon metabolites in C57BL6 old wild-type mice.

The Izpisua-Belmonte group identified a cocktail of metabolites that promote partial reprogramming in cultured muscle cells. We tested the effect of brain injection of these metabolites in the dentate gyrus of aged wild-type mice. The dentate gyrus is a brain region essential for memory function and is extremely vulnerable to aging. A single injection of the cocktail containing four compounds (putrescine, glycine, methionine and threonine) partially reversed brain aging phenotypes and epigenetic alterations in age-associated genes. Our analysis revealed three levels: chromatin methylation, RNA sequencing, and protein expression. Functional studies complemented the previous ones, showing cognitive improvement. In summary, we report the reversal of various age-associated epigenetic changes, such as the transcription factor Zic4, and several changes related to cellular rejuvenation in the dentate gyrus (DG). These changes include increased expression of the Sox2 protein. Finally, the increases in the survival of newly generated neurons and the levels of the NMDA receptor subunit GluN2B were accompanied by improvements in both short-term and long-term memory performance. Based on these results, we propose the use of these metabolites to explore new strategies for the development of potential treatments for age-related brain diseases.

The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.

The cellular prion protein (PrPC) plays many roles in the developing and adult brain. In addition, PrPC binds to several amyloids in oligomeric and prefibrillar forms and may act as a putative receptor of abnormal misfolded protein species. The role of PrPC in tau seeding and spreading is not known. In the present study, we have inoculated well-characterized sarkosyl-insoluble fractions of sporadic Alzheimer's disease (sAD) into the brain of adult wild-type mice (Prnp+/+), Prnp0/0 (ZH3 strain) mice, and mice over-expressing the secreted form of PrPC lacking their GPI anchor (Tg44 strain). Phospho-tau (ptau) seeding and spreading involving neurons and oligodendrocytes were observed three and six months after inoculation. 3Rtau and 4Rtau deposits from the host tau, as revealed by inoculating Mapt0/0 mice and by using specific anti-mouse and anti-human tau antibodies suggest modulation of exon 10 splicing of the host mouse Mapt gene elicited by exogenous sAD-tau. However, no tau seeding and spreading differences were observed among Prnp genotypes. Our results show that PrPC does not affect tau seeding and spreading in vivo.

Clicking gallic acid into chitosan prolongs its antioxidant activity and produces intracellular Ca2+ responses in rat brain cells.

Gallic acid is a vegetable-derived and highly bioactive phenolic acid, but its antioxidant capacity is sensitive to environmental conditions. Chitosan is a biopolymer capable of exerting significant protection to various molecules, including phenolic compounds. A chitosan derivative that extends the antioxidant activity of gallic acid was synthesized by click chemistry and characterized by FT-IR, 1H NMR, and antioxidant capacity assays. Our results show that synthesized polymeric solutions and nanoparticles of N-(gallic acid) chitosan were both internalized by rat brain cells, processes that were modulated by extracellular Ca2+ and Na+. Their internalization was supported by dynamic light scattering and ζ-potential analyses, while Ca2+ imaging recordings performed in brain cells revealed the potential biological effect of N-(gallic acid) chitosan. We conclude that the synthesis of an N-(gallic acid) chitosan derivative through click chemistry is viable and may serve as strategy to prolong its antioxidant activity and to study its biological effects in vivo.

Phase Angle and Body Composition as Predictors of Fitness and Athletic Performance in Adolescent Boxers.

BACKGROUND: Phase angle (PhA) is an indicator of cellular health, function, and integrity. PhA has been considered an indicator of nutritional and health status, but it is uncertain whether it could be used as a fitness or athletic performance indicator. OBJECTIVE: To analyze the relationship between PhA and the fitness and athletic performance of adolescent boxers and to know whether this association is independent of body composition. METHODS: Thirty-seven trained youth boxers (15-18 y old) participated in the study. Participants underwent anthropometry and bioelectrical impedance assessments. The following tests were conducted: Fitness-Gram battery; speed, agility, and quickness; ball throws; punch impact force; bench press maximal strength; and vertical and horizontal jumps. Linear regression models were estimated and adjusted by covariates. RESULTS: The PhA was related to upper-limb strength. Nevertheless, in linear regression models, after adjusting models by body composition, only PhA remained as a predictor of relative maximal strength. The PhA was not a predictor of speed, agility, and quickness; cardiorespiratory fitness; or lower-limb power, in which adiposity was the main predictor of fitness. CONCLUSIONS: In adolescent boxers, PhA can predict upper-limb maximal strength independently of bioelectrical impedance analysis premises. However, compared with mucle mass, PhA is not a better predictor of upper-limb maximal strength.

Delaying Brain Aging or Decreasing Tau Levels as Strategies to Prevent Alzheimer's Disease: In Memoriam of Mark A. Smith.

Aging is the main risk for neurodegenerative disorders like Alzheimer's disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer's disease.

In vivo cyclic overexpression of Yamanaka factors restricted to neurons reverses age-associated phenotypes and enhances memory performance.

In recent years, there has been success in partially reprogramming peripheral organ cells using cyclic Yamanaka transcription factor (YF) expression, resulting in the reversal of age-related pathologies. In the case of the brain, the effects of partial reprogramming are scarcely known, and only some of its effects have been observed through the widespread expression of YF. This study is the first to exclusively partially reprogram a specific subpopulation of neurons in the cerebral cortex of aged mice. The in vivo model demonstrate that YF expression in postmitotic neurons does not dedifferentiate them, and it avoids deleterious effects observed with YF expression in other cell types. Additionally, our study demonstrates that only cyclic, not continuous, expression of YF result in a noteworthy enhancement of cognitive function in adult mice. This enhancement is closely tied to increased neuronal activation in regions related to memory processes, reversed aging-related epigenetic markers and to increased plasticity, induced by the reorganization of the extracellular matrix. These findings support the therapeutic potential of targeted partial reprogramming of neurons in addressing age-associated phenotypes and neurodegenerative diseases correlated with aging.

Role of folate receptor α in the partial rejuvenation of dentate gyrus cells: Improvement of cognitive function in 21-month-old aged mice.

Neuronal aging may be, in part, related to a change in DNA methylation. Thus, methyl donors, like folate and methionine, may play a role in cognitive changes associated to neuronal aging. To test the role of these metabolites, we performed stereotaxic microinjection of these molecules into the dentate gyrus (DG) of aged mice (an average age of 21 month). Folate, but not S-Adenosyl-Methionine (SAM), enhances cognition in aged mice. In the presence of folate, we observed partial rejuvenation of DG cells, characterized by the expression of juvenile genes or reorganization of extracellular matrix. Here, we have also tried to identify the mechanism independent of DNA methylation, that involve folate effects on cognition. Our analyses indicated that folate binds to folate receptor α (FRα) and, upon folate binding, FRα is transported to cell nucleus, where it is acting as transcription factor for expressing genes like SOX2 or GluN2B. In this work, we report that a FRα binding peptide also replicates the folate effect on cognition, in aged mice. Our data suggest that such effect is not sex-dependent. Thus, we propose the use of this peptide to improve cognition since it lacks of folate-mediated side effects. The use of synthetic FRα binding peptides emerge as a future strategy for the study of brain rejuvenation.

Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3.

BACKGROUND: Tau is a microtubule-binding protein encoded by the MAPT gene. Tau is essential for several physiological functions and associated with pathological processes, including Alzheimer's disease (AD). Six tau isoforms are typically described in the central nervous system, but current research paints a more diverse landscape and a more nuanced balance between isoforms. Recent work has described tau isoforms generated by intron 11 and intron 12 retention. This work adds to that evidence, proving the existence of MAPT transcripts retaining intron 3. Our aim is to demonstrate the existence of mature MAPT RNA species that retain intron 3 in human brain samples and to study its correlation with Alzheimer's disease across different regions. METHODS: Initial evidence of intron-3-retaining MAPT species come from in silico analysis of RNA-seq databases. We further demonstrate the existence of these mature RNA species in a human neuroepithelioma cell line and human brain samples by quantitative PCR. We also use digital droplet PCR to demonstrate the existence of RNA species that retain either intron 3, intron 12 or both introns. FINDINGS: Intron-3-retaining species are even more prominently present that intron-12-retaining ones. We show the presence of MAPT transcripts that retain both introns 3 and 12. These intron-retaining species are diminished in brain samples of patients with Alzheimer's disease with respect to individuals without dementia. Conversely, relative abundance of intron-3- or intron-12-retaining MAPT species with respect to double-retaining species as well as their percentage of expression with respect to total MAPT are increased in patients with Alzheimer's disease, especially in hippocampal samples. Among these TIR-MAPT species, TIR3+12 double truncation allows better classification potential of Alzheimer's disease samples. Moreover, we find a significant increase in intron-3- or intron-12-retaining species and its relative abundance with respect to double-retaining MAPT species in cerebellum in contrast to frontal lateral cortex and hippocampus in individuals with no signs of dementia. INTERPRETATION: Intron retention constitutes a potential mechanism to generate Tau isoforms whose mature RNA expression levels correlate with Alzheimer's pathology showing its potential as a biomarker associated to the disease. FUNDING: This research was funded by the Spanish Ministry of Science, Innovation and Universities: PGC2018-096177-B-I00 (J.A.); Spanish Ministry of Science and Innovation (MCIN): PID2020-113204GB-I00 (F.H.) and PID2021-123859OB-100 from MCIN/AEI/10.13039/501100011033/FEDER, UE (J.A.). It was also supported by CSIC through an intramural grant (201920E104) (J.A.) and the Centre for Networked Biomedical Research on Neurodegenerative Diseases (J.A.). The Centro de Biología Molecular Severo Ochoa (CBMSO) is a Severo Ochoa Center of Excellence (MICIN, award CEX2021-001154-S).

Tridimensional Structural Analysis of Tau Isoforms Generated by Intronic Retention.

Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease. Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms. Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro.

Lamivudine (3TC), a Nucleoside Reverse Transcriptase Inhibitor, Prevents the Neuropathological Alterations Present in Mutant Tau Transgenic Mice.

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models as well as in human tauopathies. In this context, we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheimer's disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology.

Memory, Sleep, and Tau Function.

Memory consolidation related to the hippocampal-cortex connection takes place during sleep. This connection may involve at least two steps- one in the NREM phase of sleep (transmission) and the other in the REM phase (consolidation). In this brief report, we comment on the role of tau protein in these two phases of sleep. The absence of tau decreases δ waves in NREM, whereas the overexpression of modified (phosphorylated and/or mutated) tau alters θ waves in REM.

Gut Microbiota, an Additional Hallmark of Human Aging and Neurodegeneration.

Gut microbiota represents a diverse and dynamic population of microorganisms harbouring the gastrointestinal tract, which influences host health and disease. Bacterial colonization of the gastrointestinal tract begins at birth and changes throughout life, with age being one of the conditioning factors for its vitality. Aging is also a primary risk factor for most neurodegenerative diseases. Among them, Alzheimers disease (AD) is probably the one where its association with a state of dysbiosis of the gut microbiota has been most studied. In particular, intestinal microbial-derived metabolites have been associated with ß-amyloid formation and brain amyloid deposition, tau phosphorylation, as well as neuroinflammation in AD patients. Moreover, it has been suggested that some oral bacteria increase the risk of developing AD. However, the causal connections among microbiome, amyloid-tau interaction, and neurodegeneration need to be addressed. This paper summarizes the emerging evidence in the literature regarding the link between the oral and gut microbiome and neurodegeneration with a focus on AD. Taxonomic features of bacteria as well as microbial functional alterations associated with AD biomarkers are the main points reviewed. Data from clinical studies as well as the link between microbiome and clinical determinants of AD are particularly emphasized. Further, relationships between gut microbiota and age-dependent epigenetic changes and other neurological disorders are also described. Together, all this evidence suggests that, in some sense, gut microbiota can be seen as an additional hallmark of human aging and neurodegeneration.

Caracterización de la vida sexual de adultos mayores de un área de salud

Fundamento: la sexualidad en el anciano es un factor esencial en el mantenimiento de su calidad de vida. Objetivo: caracterizar la vida sexual de adultos mayores de un área de salud. Métodos: se realizó un estudio descriptivo y trasversal en el consultorio 163 del Policlínico Universitario Raúl Sánchez, de Pinar del Río en el periodo comprendido entre septiembre del 2020 y septiembre del 2021. El universo de trabajo estuvo integrado por 104 adultos mayores y la muestra por 72 ancianos, seleccionados mediante muestreo intencional por criterios. El instrumento utilizado fue la entrevista; los datos obtenidos fueron llevados a una encuesta que con preguntas cerradas fue aplicado personalmente a cada uno de los integrantes del estudio. Se analizaron las siguientes variables: sexo, estado civil, escolaridad, vida sexual, técnicas sexuales preferidas, funcionamiento sexual, causas que impiden la realización del acto sexual, enfermedades asociadas y consumo de medicamentos. Resultados: existió predominio del nivel de escolaridad primario, el estado civil sin parejas, el sexo femenino y la inactividad sexual; prevaleció el coito vaginal como forma más frecuente de manifestar la actividad sexual. Más del 90 % de los hombres presenta alguna dificultad en la vida sexual. El 22, 5 % presenta dificultades debido a enfermedades orgánicas. Conclusiones: es falso que el anciano sea un ente desprovisto de interés por la vida sexual, pero está afectada por varios factores, entre los que destacan las enfermedades orgánicas y la falta de pareja.

Background: sexuality in the elderly is an essential factor in maintaining their quality of life. Objective: to characterize the sexual life of older adults in a health area. Methods: a descriptive and cross-sectional study was carried out in office 163 of the Raúl Sánchez University Polyclinic, in Pinar del Río in the period between September 2020 and September 2021. The universe of work was made up of 104 older adults and the sample consisted of 72 elderly, by means of intentional sampling by criteria. The instrument used was the interview; the data obtained were taken to a survey that with closed questions was personally applied to each of the study members. The following variables were analyzed: sex, marital status, education, sexual life, preferred sexual techniques, sexual functioning, causes that prevent the performance of the sexual act, associated diseases and drug use. Results: there was a predominance of primary school level, marital status without partners, female sex and sexual inactivity; vaginal intercourse predominated as the most frequent way of manifesting sexual activity. More than 90 % of men have some difficulty in sexual life. 22.5% present difficulties due to organic diseases. Conclusions: it is false that the elderly is an entity devoid of interest in sexual life, but it is affected by several factors, among which organic diseases and lack of a partner stand out.

Neuronal nuclear tau and neurodegeneration.

Tau is a well-known microtubule-associated protein related to its cytoplasmic localization in a neuronal cell. However, tau has been located at the cell nucleus where it could be a nucleic acid-associated protein by its preferential binding to DNA sequences present in the nucleolus and pericentromeric heterochromatin. This less well-known localization of tau could not be trivial, since during aging, an increase in the amount of nuclear tau takes place and it may be related to the described role of tau in the activation of transposons and further aging acceleration.

Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice.

N-methyl-d-aspartate receptors (NMDARs) are pivotal players in the synaptic transmission and synaptic plasticity underlying learning and memory. Accordingly, dysfunction of NMDARs has been implicated in the pathophysiology of Alzheimer disease (AD). Here, we used histoblot and sodium dodecylsulphate-digested freeze-fracture replica labelling (SDS-FRL) techniques to investigate the expression and subcellular localisation of GluN1, the obligatory subunit of NMDARs, in the hippocampus of P301S mice. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus of P301S mice in a laminar-specific manner at 10 months of age but was unaltered at 3 months. Using the SDS-FRL technique, excitatory synapses and extrasynaptic sites on spines of pyramidal cells and interneuron dendrites were analysed throughout all dendritic layers in the CA1 field. Our ultrastructural approach revealed a high density of GluN1 in synaptic sites and a substantially lower density at extrasynaptic sites. Labelling density for GluN1 in excitatory synapses established on spines was significantly reduced in P301S mice, compared with age-matched wild-type mice, in the stratum oriens (so), stratum radiatum (sr) and stratum lacunosum-moleculare (slm). Density for synaptic GluN1 on interneuron dendrites was significantly reduced in P301S mice in the so and sr but unaltered in the slm. Labelling density for GluN1 at extrasynaptic sites showed no significant differences in pyramidal cells, and only increased density in the interneuron dendrites of the sr. This differential alteration of synaptic versus extrasynaptic NMDARs supports the notion that the progressive accumulation of phospho-tau is associated with changes in NMDARs, in the absence of amyloid-ß pathology, and may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit.

Tau Aggregation.

Here we revisit tau protein aggregation at primary, secondary, tertiary and quaternary structures. In addition, the presence of non-aggregated tau protein, which has been recently discovered, is also commented on.