Browsing by Keyword "Human brain"
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Publication Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients.(2019-10-09) Sanchez-Mejias, Elisabeth; Nuñez-Diaz, Cristina; Sanchez-Varo, Raquel; Gomez-Arboledas, Angela; Garcia-Leon, Juan Antonio; Fernandez-Valenzuela, Juan Jose; Mejias-Ortega, Marina; Trujillo-Estrada, Laura; Baglietto-Vargas, David; Moreno-Gonzalez, Ines; Davila, Jose Carlos; Vitorica, Javier; Gutierrez, AntoniaNeuronal loss is the best neuropathological substrate that correlates with cortical atrophy and dementia in Alzheimer's disease (AD). Defective GABAergic neuronal functions may lead to cortical network hyperactivity and aberrant neuronal oscillations and in consequence, generate a detrimental alteration in memory processes. In this study, using immunohistochemical and stereological approaches, we report that the two major and non-overlapping groups of inhibitory interneurons (SOM-cells and PV-cells) displayed distinct vulnerability in the perirhinal cortex of APP/PS1 mice and AD patients. SOM-positive neurons were notably sensitive and exhibited a dramatic decrease in the perirhinal cortex of 6-month-old transgenic mice (57% and 61% in areas 36 and 35, respectively) and, most importantly, in AD patients (91% in Braak V-VI cases). In addition, this interneuron degenerative process seems to occur in parallel, and closely related, with the progression of the amyloid pathology. However, the population expressing PV was unaffected in APP/PS1 mice while in AD brains suffered a pronounced and significant loss (69%). As a key component of cortico-hippocampal networks, the perirhinal cortex plays an important role in memory processes, especially in familiarity-based memory recognition. Therefore, disrupted functional connectivity of this cortical region, as a result of the early SOM and PV neurodegeneration, might contribute to the altered brain rhythms and cognitive failures observed in the initial clinical phase of AD patients. Finally, these findings highlight the failure of amyloidogenic AD models to fully recapitulate the selective neuronal degeneration occurring in humans.Publication Highly efficient generation of human Cerebral Organoids bypassing embryoid body stage(Elsevier, 2023) González-Sastre, Rosa; Coronel Lopez, Raquel; Bernabeu-Zornoza, Adela; Rosca, Andreea; Mateos-Martínez, Patricia; Maeso, Laura; Martín Benito, Sabela; López-Alonso, Victoria; Liste, IsabelHuman cerebral organoids (hCOs) are a promising in vitro model that may overcome some of the limitations that currently exist when studying human brain development and disease. Since Lancaster et al. first generated hCOs, efforts have been made to better recapitulate the physiology of the human brain and improve the efficiency and reproducibility of protocols. Different groups employed dual-SMAD inhibition (double inhibition of the transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) pathways) to achieve rapid neural induction. The method developed here, outlines the generation of homogeneous organoids by rapid neuroepithelial induction, avoiding the Embryoid Body (EB) stage. The efficiency of this protocol to form neuroepithelial structures and subsequently organoids is almost 100% due to the use of dual-SMAD inhibition in combination with CHIR99021 (a GSK3β inhibitor/Wnt activator) at the neural induction stage. This is a simple and reproducible protocol as we do not need to use Matrigel or bioreactors which standardizes the methodology. It is also a robust protocol as we have successfully performed it on human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). We performed IHC and Q-RT-PCR assays for cell cycle, neural precursors, neuronal and synaptic vesicle markers. The generated hCOs are highly homogeneous and show ventricular zones (VZs) with radial glia in the center that differentiate to give rise to neurons located around these VZs. These neurons acquire a mature state and are able to form synapses. In addition, we also performed IHC and Q-RT-PCR assays for different markers of oligodendrocytes, astrocytes, microglial cells and vasculature obtaining promising results. We believe that this protocol will be a breakthrough in the generation of organoids for use as a model for the study of neurodevelopmental and neurological diseases, as well as for drug testing.Publication Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.(2016-10-14) Sanchez-Mejias, Elisabeth; Navarro, Victoria; Jimenez, Sebastian; Sanchez-Mico, Maria; Sanchez-Varo, Raquel; Nuñez-Diaz, Cristina; Trujillo-Estrada, Laura; Davila, Jose Carlos; Vizuete, Marisa; Gutierrez, Antonia; Vitorica, JavierThe role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.