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Ferrer, Isidro, Andrés-Benito, Pol, Sala-Jarque, Julia, Gil, Vanessa, del Rio, José Antonio, (2020). Capacity for seeding and spreading of argyrophilic grain disease in a wild-type murine model; Comparisons with primary age-related tauopathy Frontiers in Molecular Neuroscience 13, 101

Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from “pure” AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models.

Keywords: Argyrophilic grain disease, Tauopathies, Tau, Seeding, Progression, Coiled Bodies, Primary age-related tauopathy

Campillo, N., Falcones, B., Otero, J., Colina, R., Gozal, D., Navajas, D., Farré, R., Almendros, I., (2019). Differential oxygenation in tumor microenvironment modulates macrophage and cancer cell crosstalk: Novel experimental settingand proof of concept Frontiers in Oncology 9, 43

Hypoxia is a common characteristic of many solid tumors that has been associated with tumor aggressiveness. Limited diffusion of oxygen generates a gradient of oxygen availability from the blood vessel to the interstitial space and may underlie the recruitment of macrophages fostering cancer progression. However, the available data based on the recruitment of circulating cells to the tumor microenvironment has been so far carried out by conventional co-culture systems which ignore the hypoxic gradient between the vessel to the tumor interstitium. Here, we have designed a novel easy-to-build cell culture device that enables evaluation of cellular cross-talk and cell migration while they are being simultaneously exposed to different oxygenation environments. As a proof-of-concept of the potential role of differential oxygenation among interacting cells we have evaluated the activation and recruitment of macrophages in response to hypoxic melanoma, breast, and kidney cancer cells. We found that hypoxic melanoma and breast cancer cells co-cultured with normoxic macrophages enhanced their directional migration. By contrast, hypoxic kidney cells were not able to increase their recruitment. We also identified well-described hypoxia-induced pathways which could contribute in the immune cell recruitment (VEGFA and PTGS2 genes). Moreover, melanoma and breast cancer increased their proliferation. However, oxygenation levels affected neither kidney cancer cell proliferation nor gene expression, which in turn resulted in no significant changes in macrophage migration and polarization. Therefore, the cell culture device presented here provides an excellent opportunity for researchers to reproduce the in vivo hypoxic gradients in solid tumors and to study their role in recruiting circulating cells to the tumor in specific types of cancer.

Keywords: Hypoxia gradient, Macrophage motility, Models of host-tumor interactions, Novel assay technology, Tumor progression