Lipocalin 2 contributes to brain iron dysregulation but does not affect cognition, plaque load, and glial activation in the J20 Alzheimer mouse model

BackgroundLipocalin 2 (Lcn2) is an acute-phase protein implicated in multiple neurodegenerative conditions. Interestingly, both neuroprotective and neurodegenerative effects have been described for Lcn2. Increased Lcn2 levels were found in human post-mortem Alzheimer (AD) brain tissue, and in vitro studies indicated that Lcn2 aggravates amyloid--induced toxicity. However, the role of Lcn2 has not been studied in an in vivo AD model. Therefore, in the current study, the effects of Lcn2 were studied in the J20 mouse model of AD.MethodsJ20 mice and Lcn2-deficient J20 (J20xLcn2 KO) mice were compared at the behavioral and neuropathological level.ResultsJ20xLcn2 KO and J20 mice presented equally strong AD-like behavioral changes, cognitive impairment, plaque load, and glial activation. Interestingly, hippocampal iron accumulation was significantly decreased in J20xLcn2 KO mice as compared to J20 mice.ConclusionsLcn2 contributes to AD-like brain iron dysregulation, and future research should further explore the importance of Lcn2 in AD

A construção da União Europeia no decorrer de seus tratados instituidores

Resumo: Este estudo apresenta o percurso de construção da União Europeia ao longo dos sucessivos Tratados, demonstrando a formação de suas competências e de seu aparato institucional. Também indica de que maneira o constante conflito entre posição supranacionalista, de um lado, e intergovernamentalista, de outro, implicou num processo de integração nem sempre incontroverso, mas contínuo. Será possível verificar, assim, como a União Europeia tem progressivamente ampliado sua esfera de poder e exigido um número cada vez maior atribuições, em razão das contingências oriundas da vida no bloco. De tal constatação, tornar-se-á mais clara a conclusão de que, hoje, a solução de muitos problemas nacionais e europeus já não pode ser pensada sem uma atuação ao menos conjunta da União Europeia, tendo em vista a profundidade dos vínculos entre os Estados-membros e o grande número de ferramentas titularizadas pelo ente supraestata

Muros e pontes : do direito à literatura

Orientador: Vera Karam de Chueiri. Coorientador: Daniel Wunder HachemMonografia (graduação) - Universidade Federal do Paraná, Setor de Ciências Jurídicas, Curso de Graduação em Direit

On the Dissimilarity of 5′-AMP Induced Hypothermia and Torpor in Mice

Administration of adenosine-5′-monophosphate (5′-AMP) can induce an artificial but endogenously reversible torpor-like state in mice. The dynamics of body temperature and the relation between body temperature and metabolic rate may indicate the (dis)similarity of this artificial torpor-like state to natural torpor in intact animals. We investigated these in C57BL/6J mice by (1) comparing cooling rates during 5′-AMP induced hypothermia to cooling rates during high workload induced torpor, and by (2) estimating the relative contributions of metabolic suppression and passive temperature (Q 10) effects in the 5′-AMP induced hypothermic state. We did the latter by back-extrapolating the relation between body temperature and metabolic rate in hypothermic conditions to the euthermic temperature level, using calculated Q 10-values. The data indicate that (1) cooling rate in 5′-AMP induced hypothermia is about 1.8 times faster than in natural torpor in workload conditions, and that (2) Q 10 effects can entirely explain the metabolic reduction of 5′-AMP induced hypothermia, indicating that active metabolic suppression may be lacking. Together, this suggests fundamental differences between 5′-AMP induced hypothermia and natural torpor, limiting the validity of the paradigm to the study of effects of hypothermic conditions and temperature related metabolic effects

Activity-state profile of tau kinases in hibernating animals

A variety of neurological disorders including Alzheimer's disease are associated with the formation of neurofibrillary tangles, made up by intraneuronal paired helical filaments (PHFs) that are composed of hyperphosphorylated tau protein. The phosphorylation of tau is assumed to be crucial for aggregation; however, the underlying mechanisms are not well understood. Several kinases have been identified as potential candidates for the abnormal phosphorylation under pathological conditions. Nevertheless, based on the lack of appropriate models the actual relevance of these enzymes could not be studied concertedly under physiological conditions. Recently, we described the reversible formation of highly phosphorylated tau protein in hibernating animals under physiological conditions. Using hibernation as a model we determined the activity profile of four major tau kinases in three different species to analyse the state-dependent regulation of these enzymes and reveal the importance of each kinase for tau phosphorylation

The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress

The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases. © 2014 Macmillan Publishers Limited All rights reserved

On the Dissimilarity of 5′-AMP Induced Hypothermia and Torpor in Mice

Administration of adenosine-5′-monophosphate (5′-AMP) can induce an artificial but endogenously reversible torpor-like state in mice. The dynamics of body temperature and the relation between body temperature and metabolic rate may indicate the (dis)similarity of this artificial torpor-like state to natural torpor in intact animals. We investigated these in C57BL/6J mice by (1) comparing cooling rates during 5′-AMP induced hypothermia to cooling rates during high workload induced torpor, and by (2) estimating the relative contributions of metabolic suppression and passive temperature (Q 10) effects in the 5′-AMP induced hypothermic state. We did the latter by back-extrapolating the relation between body temperature and metabolic rate in hypothermic conditions to the euthermic temperature level, using calculated Q 10-values. The data indicate that (1) cooling rate in 5′-AMP induced hypothermia is about 1.8 times faster than in natural torpor in workload conditions, and that (2) Q 10 effects can entirely explain the metabolic reduction of 5′-AMP induced hypothermia, indicating that active metabolic suppression may be lacking. Together, this suggests fundamental differences between 5′-AMP induced hypothermia and natural torpor, limiting the validity of the paradigm to the study of effects of hypothermic conditions and temperature related metabolic effects