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Purpose of review. All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual’s genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer’s disease and related dementia (ADRD) cases. Recent findings. Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss. Summary. While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunologi

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunologi

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunologi

Tres millones y medio de familias no tienen acceso a una vivienda digna en Argentina. En el Centro Experimental de la Vivienda Económica se diseñan soluciones constructivas destinadas a la vivienda social apropiadas y apropiables. Un ejemplo son los ladrillos de PET reciclado y cemento, que pueden utilizarse como mampostería no portante. A pesar del interés de la tecnología desarrollada por el CEVE y transferida a distintos emprendimientos municipales para su implementación, se comprueba que el 93% de los emprendimientos abandona la fabricación tras las capacitaciones. Esta investigación pretende identificar las dificultades a las que se enfrentan los emprendimientos para el abandono de la práctica constructiva y propone una formulación de ladrillo mejorada, que facilita el proceso de producción. El impacto principal del proyecto se dirige a los emprendimientos locales y a la posibilidad de reutilizar un material no biodegradable como el plástico, en lugar de que termine en nuestros océanos. En la búsqueda de la mezcla más adecuada en términos de resistencia mecánica y de costes, se realizan distintos tipos de ensayos con PET de diferentes granulometrías, mezclado con agregados como Residuos de Construcción y Demolición así como la incorporación de agregados aligerados. De la investigación se desprende que el tipo de mezcla con mejor funcionamiento es la conformada por partículas de PET grueso con RCD y cemento, debido a sus propiedades mecánicas: tiene una resistencia a compresión de 2MPa (cumpliendo con la normativa de mampostería no portante); y físicas: con una densidad un 40% más baja que la mezcla original, se mantienen las propiedades de aislamiento térmico. Se elige esta muestra como la más favorable a la necesidad planteada a partir de las entrevistas con los emprendimientos.

Cylindrospermopsin (CYN) is a cyanotoxin whose incidence has been increasing in the last decades. Due to its capacity to exert damage at different levels of the organism, it is considered a cytotoxin. Although the main target organ is the liver, recent studies indicate that CYN has potential toxic effects on the nervous system, both in vitro and in vivo. Thus, the aim of the present work was to study the effects of this cyanotoxin on neuronal viability and synaptic integrity in murine primary cultures of neurons exposed to environmentally relevant concentrations (0–1 µg/mL CYN) for 12, 24, and 48 h. The results demonstrate a concentration-and time-dependent decrease in cell viability; no cytotoxicity was detected after exposure to the cyanotoxin for 12 h, while all of the concentrations assayed decreased this parameter after 48 h. Furthermore, CYN was also demonstrated to exert damage at the synaptic level in a murine primary neuronal culture in a concentration-and timedependent manner. These data highlight the importance of studying the neurotoxic properties of this cyanotoxin in different experimental models.

Additional File 1: Table S1. Demographic and neuropathological characteristics of study subjects. Description: Abbreviations: ADNC = AD neuropathological changes; APOE = Apolipoprotein E genotype; CAA = cerebral amyloid angiopathy; CVD = cerebrovascular disease; F = female; LBD = Lewy body disease; M = male; NA = Not available/applicable; NOS = not otherwise specified; NP Dx = neuropathological diagnosis. Table S2. Primary and secondary antibodies used in this study and sequence of immunohistochemistry cycles. Description: Note: GFAP and DAPI detection are needed in all the cycles to guarantee an adequate alignment of the images. Abbreviations: AF488 = AlexaFluor 488; Cy = cyanine; Dk = donkey; Gt = goat; Ms = mouse; Rb = rabbit. All secondary antibodies were purchased from Jackson ImmunoResearch Labs, West Grove, PA. Table S3. Results of mixed effects regression models. Description: Results of mixed effects regression models with diagnosis (CTRL vs. AD) or state (homeostatic vs. intermediate vs. reactive) as a fixed effect, respectively, and subject ID as random effect in both cases, are reported. Table S4. Model performance statistics for CTRL vs. AD binary classifiers. Description: Model performance statistics for the binary classification task of CTRL vs. AD for both the gradient boosting machine (GBM) and the convolutional neural network (CNN) machine learning models are reported. For all heuristics except for AUC and AUCPR (which are not threshold-dependent), the threshold was chosen by maximizing the accuracy. 95% confidence intervals were estimated by bootstrapping the hold-out test set across 500 iterations. Table S5. Results of Bayesian hyperparameter optimization. Description: The final hyperparameters determined by the Optuna hyperparameter tuning framework are reported. The Optuna optimizer maximized the out-of-sample area under the receiver operating characteristic (ROC) curve (AUC), which in turn was determined by 3-fold cross-validation for each tria

Cylindrospermopsin (CYN) is a cyanotoxin whose incidence has been increasing in the last decades. Due to its capacity to exert damage at different levels of the organism, it is considered a cytotoxin. Although the main target organ is the liver, recent studies indicate that CYN has potential toxic effects on the nervous system, both in vitro and in vivo. Thus, the aim of the present work was to study the effects of this cyanotoxin on neuronal viability and synaptic integrity in murine primary cultures of neurons exposed to environmentally relevant concentrations (0–1 µg/mL CYN) for 12, 24, and 48 h. The results demonstrate a concentration- and time-dependent decrease in cell viability; no cytotoxicity was detected after exposure to the cyanotoxin for 12 h, while all of the concentrations assayed decreased this parameter after 48 h. Furthermore, CYN was also demonstrated to exert damage at the synaptic level in a murine primary neuronal culture in a concentration- and time-dependent manner. These data highlight the importance of studying the neurotoxic properties of this cyanotoxin in different experimental models.