Suchergebnisse

In this article, Serrano, Ávila and colleagues show that cyclic expression of Yamanaka factors Oct4, Sox2, Klf4, and c-Myc in the hippocampus prevent the age-dependent reduction in the epigenetic marker H3K9 trimethylation (H3K9me3) and alter adult hippocampal neurogenesis. These cellular changes were accompanied by an improvement in mouse performance in the object recognition test.Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases. ; Spanish Ministry of Economy and Competitiveness (PGC-2018-09177-B-100) and Centro de Investigacio´n Biome´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII). Spanish Ministry of Economy and Competitiveness (BFU2016-77885-P) and Comunidad de Madrid co-financed with the Structural Funds of the European Union (S2017/BMD-3700 (NEUROMETAB-CM)). Work in the laboratory of M.S. was funded by the IRB and by grants from the MINECO co-funded by the European Regional Development Fund (SAF2017-82613-R), the European Research Council (ERC-2014-AdG/669622), and ''La Caixa'' Foundation. An institutional grant from the Fundación Ramón Areces to the CBMSO

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

14 p.-5 fig. ; Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer's and Huntington's, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism. ; This work was supported by funding from the Sixth Framework Programme (MIRG-CT-2004-014567, to D.C.H.) a IRCSET-Marie Curie International Mobility Fellowship, the Health Research Board (PD/2009/31 to T.E. and HRA_POR/ 2011/41 to D.C.H.); Science Foundation Ireland (13/SIRG/2098 and 17/CDA/ 4708 to T.E. and 16/RC/3948 to D.C.H.) and co-funded under the European Regional Development Fund and by FutureNeuro industry partners;); from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (753527 to E.B.); from the European Union's Horizon 2020 research and innovation programme under the Marie Sklowdowska-Cuire grant agreement (No. 766124 to T.E.); grants from Ministerio de Economía Industria y Competitividad of Spain SAF2009-08233 and SAF2015-65371-R to J.J.L., SAF2016-78603-R to M.M. and BFU2016-77885-P to F.H.; grant PI2015-2/06-3 from CIBERNED-ISCIII to J.J.L.; and institutional grants to CBMSO from Fundación Ramón Areces and Fundación Banco de Santander. ; Peer reviewed