Late-life depression accelerates cognitive decline in a tauopathy mouse model

Background: Clinical studies suggest that depressive symptoms could be considered an important risk factor for the future development of cognitive impairment and even Alzheimer's disease (AD). In fact, there is a strong association between depression in later life and AD. The age of onset of AD has been shown to be accelerated in patients with mild cognitive impairment (MCI) with a history of depression, and women appear to be particularly more vulnerable to this condition. In addition, individuals with MCI who present depressive symptoms have an elevated burden of amyloid-beta, one of the featured toxic proteins associated with Alzheimer's pathology, and a higher risk of developing AD compared to non-depressed MCI patients. Although it has been described that some transgenic models of AD can develop signs similar to depression in advanced stages, it is unknown whether late-life depression can accelerate tau-associated pathology and, therefore, acting as a risk factor for AD. Method: In this study, we induced chronic unpredictable mild stress (CUMS) in P301S tau transgenic mice to determine whether depression is a cause, rather than a consequence, of the development of AD. Result: The results of our study indicate that the induction of CUMS in transgenic animals induces phenotypic changes related to a depressive state. Conclusion: The findings obtained after inducing late-life depression-like in P301S mice indicate that depression could be considered a risk factor for AD, by accelerating tau aggregation and worsening clinical signs.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Late-life depression accelerates cognitive impairment and tau-associated pathology in an Alzheimer´s disease model.

Clinical studies suggest that depression could be considered an important risk factor for the future development of cognitive impairment and Alzheimer's disease (AD). In fact, there is a strong association between late-life depression and AD. The age of AD onset has been shown to be accelerated in patients with mild cognitive impairment (MCI) with a history of depression, and women appear to be particularly more vulnerable to this condition. In addition, individuals with MCI who present depressive symptoms have an elevated burden of amyloid-beta (Aβ), the main toxic protein associated with Alzheimer's pathology, and a higher risk of developing AD compared to non-depressed MCI patients. Although it has been described that some transgenic models of AD can develop signs similar to depression in advanced stages, the induction of Alzheimer's pathology due to a depressive process has not been studied under experimental conditions to emulate late-life depression as a risk factor for AD. In this study, we induced chronic unpredictable mild stress (CUMS) in P301S tau transgenic mice to determine whether depression is a cause, rather than a consequence, of the development of AD pathology. Our results suggest that transgenic tau mice subjected to CUMS seem to develop a depressive state. This animals display enhanced cognitive impairment compared to controls. In addition, histological studies show increased tau deposition, suggesting that late-life depression could worse AD progression by accelerating tau aggregation and worsening clinical signs. The findings generated in this project could provide evidence of depression as a risk factor for AD, providing new insights on molecular mechanisms involved in AD onset and progression.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Cognitive impairment acceleration after late-life depression in a model of Alzheimer´s disease

Background: Clinical studies suggest that depressive symptoms could be considered an important risk factor for the future development of cognitive impairment and even Alzheimer's disease (AD). In fact, there is a strong association between depression in later life and AD. The age of onset of AD has been shown to be accelerated in patients with mild cognitive impairment (MCI) with a history of depression, and women appear to be particularly more vulnerable to this condition. In addition, individuals with MCI who present with depressive symptoms have an elevated burden of amyloid-beta (Aβ), the main toxic protein associated with Alzheimer's pathology, and a higher risk of developing AD compared to non-depressed MCI patients. However, it is unknown whether depression can be considered a risk factor for the development of AD. Although it has been described that some transgenic models of AD can develop signs similar to depression in advanced stages, the induction of Alzheimer's pathology due to a depressive process has not been studied under experimental conditions to emulate late-life depression as a risk factor for AD. Method: In this study, we induced chronic unpredictable mild stress (CUMS) in P301S tau transgenic mice to determine whether depression is a cause, rather than a consequence, of the development of AD. Result: The results of our study indicate that the induction of CUMS in transgenic animals of the disease give rise to changes in depressive state of the animals. Conclusion: The findings generated in this project could provide evidence of depression as a risk factor for AD, its mechanisms of action, use as early biomarkers, as well as the discovery of new therapies for AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Ministerio de Ciencia e Innovación Brain and Behavior Research Foundation Fondos FEDER y Universidad de Málag

The Influence of Geographical Factors in Traditional Earthen Architecture: The Case of the Iberian Peninsula

[EN] Geographical and environmental conditions were two of the most important factors on the design and construction of traditional architecture. Traditional earthen architecture is found throughout the Iberian Peninsula in numerous constructive techniques and variants, most notably rammed-earth, adobe and half-timber. The varied morphology, climate, geology and culture of the Iberian Peninsula, together with its immediate surroundings, have a direct effect on the development and the properties of traditional architecture. Thus, the objective of this research is to establish the relationship between the geographical characteristics and the distribution of the earthen techniques. For that purpose, the authors of this text have carried out a thorough data collection throughout the whole of the Iberian Peninsula in order to identify the main characteristics of this architecture in each location and to produce maps featuring the locations for each technique. This mapping of numerous techniques has been compared with other thematic maps of the territory, establishing relationships between the different techniques and specific properties of a given area. These provide hypotheses on which factors encourage or hinder the use of earthen construction techniques. Moreover, the relationship of traditional architecture with geographical factors and its specific morphology on a given place has provided many design lessons for a sustainable architecture. Those lessons must be taken into account on rehabilitation works and new architecture.This work is part of the research project "Restoration and rehabilitation of traditional earthen architecture in the Iberian Peninsula. Guidelines and tools for a sustainable intervention", funded by the Spanish Ministry of Economy and Competitiveness (Ref.: BIA2014-55924-R; main researchers: Camilla Mileto and Fernando Vegas Lopez-Manzanares).Mileto, C.; Vegas López-Manzanares, F.; Villacampa Crespo, L.; García-Soriano, L. (2019). The Influence of Geographical Factors in Traditional Earthen Architecture: The Case of the Iberian Peninsula. Sustainability. 11(8):1-22. https://doi.org/10.3390/su11082369S122118Font, F., & Hidalgo, P. (2011). La tapia en España. Técnicas actuales y ejemplos. Informes de la Construcción, 63(523), 21-34. doi:10.3989/ic.10.015Kottek, M., Grieser, J., Beck, C., Rudolf, B., & Rubel, F. (2006). World Map of the Köppen-Geiger climate classification updated. Meteorologische Zeitschrift, 15(3), 259-263. doi:10.1127/0941-2948/2006/0130Dincyurek, O., H. Mallick, F., & Numan, I. (2003). Cultural and environmental values in the arcaded Mesaorian houses of Cyprus. Building and Environment, 38(12), 1463-1473. doi:10.1016/s0360-1323(03)00159-8Parra-Saldivar, M. L., & Batty, W. (2006). Thermal behaviour of adobe constructions. Building and Environment, 41(12), 1892-1904. doi:10.1016/j.buildenv.2005.07.021González, M. J., & García Navarro, J. (2006). Assessment of the decrease of CO2 emissions in the construction field through the selection of materials: Practical case study of three houses of low environmental impact. Building and Environment, 41(7), 902-909. doi:10.1016/j.buildenv.2005.04.006Nardi, I., Lucchi, E., de Rubeis, T., & Ambrosini, D. (2018). Quantification of heat energy losses through the building envelope: A state-of-the-art analysis with critical and comprehensive review on infrared thermography. Building and Environment, 146, 190-205. doi:10.1016/j.buildenv.2018.09.05

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling batterThis research was funded by INSTITUTO DE SALUD CARLOS III (ISCiii) of Spain, cofinanced by FEDER funds from European Union, through grants PI21/00915 (to AG) and PI21/00914 (to JV); by JUNTA DE ANDALUCIA CONSEJERÍA DE ECONOMÍA Y CONOCIMIENTO through grants UMA18-FEDERJA-211 (to AG), UMA20-FEDERJA-104 (to IMG), P18-RT-2233 (to AG) and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014–2020 and CONSEJERIA DE SALUD grant PI-0276-2018 (to JAGL); by SPANISH MINISTER OF SCIENCE AND INNOVATION grant PID2019-108911RA-100 (to DBV), BEATRIZ GALINDO PROGRAM BAGAL18/00052 (to DBV), Alzheimer Association AARG-22-928219 (to DBV), grant PID2019-107090RA-100 (to IMG) and RAMON Y CAJAL PROGRAM RYC-2017-21879 (to IMG); and by MALAGA UNIVERSITY grant B1-2019_07 (to ESM), grant B1-2020_04 (to JAGL), grant B1-2019_06 (to IMG) and NASARD grant 27565 2018 (to IMG). M.M.-O. held a predoctoral contract from Malaga University, J.J.F.-V. held a postdoctoral contract from Malaga University, and E.S.-M. a postdoctoral contract (DOC_00251) from Junta de Andalucia. Partial funding for open access charge: Universidad de Málaga

Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease

Alzheimer’s disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-β (Aβ) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aβ and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aβ pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aβ oligomers (Aβo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aβo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aβo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aβo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aβo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.España Ministry of Science and Innovation (MICIN) State Research Agency grants PID2019-107090RA-I00España Ministerio de Ciencia e Innovación, Programa Ramon y Caja RYC-2017-21879 (to IMG) and grants from NIH R01AG059321 and R01AG061069 (to CS)

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (X$_{max}$) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1-10 EeV, a new analysis technique has been developed by combining the FD-based measurement of X$_{max}$ with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy

Study on multi-ELVES in the Pierre Auger Observatory

Since 2013, the four sites of the Fluorescence Detector (FD) of the Pierre Auger Observatory record ELVES with a dedicated trigger. These UV light emissions are correlated to distant lightning strikes. The length of recorded traces has been increased from 100 μs (2013), to 300 μs (2014-16), to 900 μs (2017-present), to progressively extend the observation of the light emission towards the vertical of the causative lightning and beyond. A large fraction of the observed events shows double ELVES within the time window, and, in some cases, even more complex structures are observed. The nature of the multi-ELVES is not completely understood but may be related to the different types of lightning in which they are originated. For example, it is known that Narrow Bipolar Events can produce double ELVES, and Energetic In-cloud Pulses, occurring between the main negative and upper positive charge layer of clouds, can induce double and even quadruple ELVES in the ionosphere. This report shows the seasonal and daily dependence of the time gap, amplitude ratio, and correlation between the pulse widths of the peaks in a sample of 1000+ multi-ELVES events recorded during the period 2014-20. The events have been compared with data from other satellite and ground-based sensing devices to study the correlation of their properties with lightning observables such as altitude and polarity