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Human tauopathies, such as Alzheimer's disease (AD), have been widely studied in transgenic mice overexpressing human tau in the brain. The longest brain isoforms of Tau in mice and humans show 89% amino acid identity; however, the expression of the isoforms of this protein in the adult brain of the two species differs. Tau 3R isoforms are not present in adult mice. In contrast, the adult human brain contains Tau 3R and also Tau 4R isoforms. In addition, the N-terminal sequence of Tau protein in mice and humans differs, a Tau peptide (residues 17–28) being present in the latter but absent in the former. Here we review the main published data on this N-terminal sequence that suggests that human and mouse Tau proteins interact with different endogenous proteins and also show distinct secretion patterns ; This study was funded by grants from Spanish Ministry of Economy and Competitiveness (Ministerio de Economía, Industria y Competitividad, Gobierno de España; BFU2016-77885-P), Structural Funds of the European Union from the Comunidad de Madrid [S2017/BMD-3700 (NEUROMETAB-CM)], institutional funding from the Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R. Areces. JM-R has a fellowship from the Fundación La Caixa

It is well known that transgenic mice overexpressing human tau protein with P301S mutation driven by the mouse prion protein promoter show clasping and limb retraction, hunched back and paralysis, followed by inability to feed that results in death around 12 months of age. To understand these motor deficits, we have carried out rotarod tests on PS19 line and demonstrated how they worsened during aging. Then, we have analyzed if these phenotypic characteristics correlate with sciatic nerve degeneration. We first demonstrated by western blot and immunohistochemistry that the sciatic nerve expresses the transgenic tau protein; then, electron microscopy studies showed alterations in myelin, mainly a detachment of myelin lamellae at Schmidt-Lanterman clefts. Similar motor deficits and myelin alterations have been previously reported in tau knockout and overexpressing transgenic mice; taking into account that PS19 model is widely used to study tauopathies, we suggest that analyzing the expression of transgenic tau protein and myelin abnormalities in the sciatic nerve should be considered when studying some features as motor performance or survival. ; Spanish Ministry of Economy and Competitiveness (BFU2016-77885-P), Comunidad de Madrid cofinanced with the Structural Funds of the European Union (S2017/BMD-3700 (NEUROMETAB-CM)), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and from an institutional grant from the Fundación R. Areces

Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and newly-formed neurons were visualized using the thymidine analog iodo-deoxyuridine (IdU) and a green fluorescent protein (GFP)-expressing retrovirus to visualize the dendritic tree and synaptic spines. Using this approach, we quantified differences in the rate of neurogenesis and migration, the structure of the apical dendritic tree and density and morphology of dendritic spines in newly-formed neurons.SE resulted in an increased rate of hippocampal neurogenesis, including within the undamaged contralateral dentate gyrus (DG). Newly-formed neurons underwent aberrant migration, both within the granule cell layer and into ectopic sites. Inhibition of microRNA-22 exacerbated these changes. The dendritic diameter and the density and average volume of dendritic spines were unaffected by SE, but these parameters were all elevated in mice in which microRNA-22 was suppressed. MicroRNA-22 inhibition also reduced the length and complexity of the dendritic tree, independently of SE. These data indicate that microRNA-22 is an important regulator of morphogenesis of newly-formed neurons in adults and plays a role in supressing aberrant neurogenesis associated with SE. ; Science Foundation Ireland (13/SIRG/2098, 17/CDA/4708 and 16/TIDA/4059 to TE, 13/SIRG/2114 to EJ-M, 17/TIDA/5002 to CR, 13/IA/1891 and 16/RC/3948 to DH and co-funded under the European Regional Development Fund and by FutureNeuro Industry partners) from the Health Research Board (HRA-POR-2015-1243 to TE); European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n 602130 (to DH), from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to EB), from the European Union's Horizon 2020; Comunidad de Madrid to MM-P, from Fundación ''La Caixa'' to JM-R and from Areces Foundation C-XVIII and the Minister of Science and Universities of Spain BFU2014-53654-P to MM-P ; Peer Reviewed

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C- terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system. ; Spanish Ministry of Economy and Competitiveness (MINECO) SAF2013-45232-R and SAF2017-88089-R to Mariano Esteban; and grants from MINECO (BFU2016-77885-P and SAF-2014-53040-P), from Comunidad de Madrid co-financed with the Structural Funds of the European Union (S2017/BMD-3700 (NEUROMETAB-CM)), funds from Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and from an institutional grant from the Fundación R. Areces

Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and newly-formed neurons were visualized using the thymidine analog iodo-deoxyuridine (IdU) and a green fluorescent protein (GFP)-expressing retrovirus to visualize the dendritic tree and synaptic spines. Using this approach, we quantified differences in the rate of neurogenesis and migration, the structure of the apical dendritic tree and density and morphology of dendritic spines in newly-formed neurons.SE resulted in an increased rate of hippocampal neurogenesis, including within the undamaged contralateral dentate gyrus (DG). Newly-formed neurons underwent aberrant migration, both within the granule cell layer and into ectopic sites. Inhibition of microRNA-22 exacerbated these changes. The dendritic diameter and the density and average volume of dendritic spines were unaffected by SE, but these parameters were all elevated in mice in which microRNA-22 was suppressed. MicroRNA-22 inhibition also reduced the length and complexity of the dendritic tree, independently of SE. These data indicate that microRNA-22 is an important regulator of morphogenesis of newly-formed neurons in adults and plays a role in supressing aberrant neurogenesis associated with SE ; This work was supported by funding from Science Foundation Ireland (13/SIRG/2098, 17/CDA/4708 and 16/TIDA/4059 to TE, 13/SIRG/2114 to EJ-M, 17/TIDA/5002 to CR, 13/IA/1891 and 16/RC/3948 to DH and co-funded under the European Regional Development Fund and by FutureNeuro Industry partners) from the Health Research Board (HRA-POR-2015-1243 to TE), from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n◦ 602130 (to DH), from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to EB), from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 766124 to TE), S2013/ICE-2958 from Comunidad de Madrid to MM-P, from Fundación ''La Caixa'' to JM-R and from Areces Foundation C-XVIII and the Minister of Science and Universities of Spain BFU2014-53654-P to MM-P