Suchergebnisse

Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning. ; This work was funded by the following grants: EP-V (DGICYT BFU2011-27207 and Spanish Junta de Andalucía CTS-2257); JN-D (CONACYT postdoctoral scholarship); MP-R (Ph.D. Fellowship from the Plan Propio UPO and by a Ph.D. Fellowship from the Basque Country Government); RR (Spanish Junta de Andalucía BIO-113 and SAF2015-64171-R); JR (MINECO-AEI/FEDER, UE BFU2016-80295-R); GAT (Spanish Junta de Andalucía BIO-209 and MINECO-AEI/FEDER, UE BFU2015-64536-R); AR-M (MINECO-AEI/FEDER, UE BFU2015-68655-P and the Junta de Andalucía P11-CVI-7290); and JA (Spanish Junta de Andalucía BIO-122 and MINECO-AEI/FEDER, UE PID2019-109569GB-I00).

The legal framework for the cattle sector can also be considered as public policy for its development. This can be understood as a set of incentives and sanctions, which influences the affected actors and generates changes, not only in internal behaviours and dynamics but also in values. In 2003, Colombia's legal framework for the cattle value chain saw the beginning of a period of major transformations, but it was in 2007 when a radical and complex legislation was presented to introduce the cattle sector into the context of international trade. However, the expected changes of behaviour among actors were not fully achieved by as incompliance could and still can be observed throughout the sector. This study was conducted in 2016 and has the aim to revise the legal framework for the Colombian cattle value chain and to a) analyse the underlying complexities that came with the implementation of rigid legislative processes, and b) to identify the bottlenecks considering the aim of putting the cattle sector into a global context. The methodology consists of two steps: 1) a systematic and chronological compilation of the laws, decrees, resolutions and standards, and 2) an analysis of both the institutional and social evolution of the sector over time, as well as the advances and challenges presented in terms of e.g., traceability, hygiene, animal welfare and sustainability. First results show that although important advances have been made in order to adapt the legal framework to international requirements, these are not sufficient when adequate enforcement and control mechanisms are missing. In addition, the success of public and legislative policies depends to a great extent on the context in which they are applied and the capacities actors have to understand their complexity. This study will serve decision makers in the development of targeted follow-up and improvement processes in order to ensure future competitiveness and sustainability of the cattle sector at international level. It will also serve the value chain actors as guidance on the rules that apply for their specific activity – a valuable source of information given the fact that official information sites are often incomplete. ; Cauca Regional Government, Colombia

Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer's disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice. ; We gratefully acknowledge grant funding support from Ministry of Science and Innovation (MINECO) with exp. PID2019-104921RB-I00/MCI/AEI/10.13039/501100011033 as well as to the Foundation for Applied Medical Research, the University of Navarra (Pamplona, Spain) for financial support and the Asociación de Amigos of the University of Navarra for the grant to M.P.-G. and S.B. We also gratefully acknowledge grant funding support from Spanish Ministerio de Economía y Competitividad (RTI2018-095812-B-I00 MCIN/ AEI/10.13039/501100011033) y por FEDER una manera de hacer Europa and Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000229) to RL, from the Spanish Ministry of Science Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) to J.F.-I. and E.S and from the Department of Economic and Business Development from Government of Navarra (INNOLFACT project; Ref. 0011-1411-2020-000028).

This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications. ; In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state's proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress. ; This research and APC were funded by the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE RTI2018-098645-B-100. J.G.-R. and I.G.-D. were funded by predoctoral fellowships from Spanish Government. M.A.B was funded by the Spanish Ministerio de Economia y Competitividad (Programa Ramón y Cajal: RYC-2017-21804). MSS was funded by a Marie-Sklodowska Curie Fellowship H2020-MSCA-IF-2017-795695. ; Peer reviewed

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD. ; This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson's and Alzheimer's Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer's Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED "Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)". HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978). ; Peer reviewed