Tau deletion prevents stress-induced dendritic atrophy in prefrontal cortex: role of synaptic mitochondria

Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, awell-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause–effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition,we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation aswell as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.This work was funded by the Portuguese Foundation for Science & Technology (FCT, grant number NMC-113934 to I.S.), the EU Consortium Switchbox (grant number Health-FP7-2010-259772 to O.F.X.A. and N.S.), the Deutsche Forschungsgemeinschaft (grant number FI 1895/1-1 to M.D.F.) and the Max Planck Society (M.D.F., G.M., C.W.T., and O.F.X.A.). In addition, this workwas also co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) (N.S.). S.L. and I.S. are holders of FCT Fellowships. J.V-S. is a recipient of a PhD fellowship (PD/ BD/105938/2014) of the University of Minho MD/PhD Program funded by FCT.info:eu-repo/semantics/publishedVersio

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.work was supported by NIH grants R01NS080967and R21MH 104803 to C.L.W., Portuguese Foundation for Science & Technology (FCT) PhD fellowships to J. Vaz-Silva and T. Meira (PD/BD/105938/2014; PD/BD/113700/2015, respectively), and the following grants to I.S.: FCT Investigator grant IF/01799/2013, the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), the Project Estratégico co-funded by FCT (PEst-C/SAU/LA 0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01 -0124-FEDER-037298) as well as the project NORTE- 01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER)info:eu-repo/semantics/publishedVersio

Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology

Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.We would like to thank Professor Juergen Gotz, (University of Queensland, Australia) for the kind offer of eGFP-P301LTau SH-SY5Y cells and Dr. Bruno Almeida for his technical assistance. J.M.S. was granted with a PhD fellowship (SRFH/BD/88932/2012) by Portuguese Foundation for Science & Technology (FCT); I.S. is holder of FCT Investigator grants (IF/01799/2013), C.D. is a recipient of PhD fellowship of PHDoc program and co-tutelle PhD student of UMinho-UPMC universities. This work was funded by FCT research grants "PTDC/SAU-NMC/113934/2009" (I.S.), the Portuguese North Regional Operational Program (ON. 2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Project Estrategico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). In addition, this work was partly funded by Canon Foundation in Europe. This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145FEDER-007038. This study was also supported to BW by grants from NIH (AG050471, NS089544, and ES020395), the BrightFocus Foundation, the Alzheimer Association and the Cure Alzeimer Foundation. Human brain tissue was generously provided by the National Institute of Aging Boston University AD Center (P30AG13846).info:eu-repo/semantics/publishedVersio

As ações do stress crónico e dos glucocorticoides na plasticidade cerebral e na patologia da proteína Tau

Trabalho de Doutoramento realizado em cotutela: Doutoramento em Envelhecimento e Doenças Crónicas e École Doctorale Cerveau, Cognition, Comportement (Paris, no 158)Chronic stress and high levels of the stress hormone, glucocorticoid (GC), are implicated in susceptibility to brain pathologies such as depression or Alzheimer’s disease (AD), as they promote neural plasticity damage and glial reactivity, which can lead to dendritic/synaptic loss, reduced neurogenesis, mood deficits, and impaired cognition. Growing clinical evidence supports a pathological link between depression and AD and shared neurobiological underpinnings with chronic stress being a potential link between them. Exposure of AD animal models to chronic stress triggers Tau pathology (e.g. Tau hyperphosphorylation and accumulation); the latter is causally related to neuronal malfunction and atrophy. Despite the well-known role of Tau in regulating cytoskeletal dynamics, the involvement of Tau in neurostructural remodeling and neuroplastic damage caused by chronic stress in the adult brain remains poorly explored. In the first objective of my thesis, we demonstrated the crucial role of Tau and its malfunction in stress-driven neurogenic, but not astrogliogenic or oligodendrogenic, damage in the cytogenic niches of the adult brain of wild-type animals (hippocampus and subventricular zone-olfactory bulb system) as mice lacking Tau were protected against stress-driven neurogenic suppression. Also, we showed that chronic stress impacts differentially the distinct phases of maturation of newborn immature neurons in the adult hippocampus. The second objective of my thesis focused on the cell-specific actions of the glucocorticoid receptor, GR, in stress-induced Tau pathology. To examine the role of GR specifically in neurons or microglia under stress conditions, we generated P301LTau mice in which GR gene is conditionally inactivated either in forebrain neurons or in microglia. Our findings show that GR was required in both cell types for chronic stress to induce cognitive deficits. Further analyses (which are ongoing) showed that neuronal GR is important in precipitating Tau neuropathology, and apical spine loss in CA1 hippocampal area. Microglial GR was found to affect microglial reactivity both in response to P301LTau as well as chronic stress-induced Tau pathology. Deletion of microglial GR results in spine loss whereas, it promotes spinogenesis under stress. However, it does not appear to impact Tau aggregation/accumulation. In conclusion, our data point to an important role of neuronal GR in mediating stress-driven Tau neuropathology and also identifies the essential role of microglial GR in stress-induced cognitive deficits. Given that the modern lifestyle increasingly exposes individuals to high stress loads, it is clear that understanding the mechanistic link(s) between chronic stress and AD pathogenesis may facilitate the treatment of AD and other related disorders.O stress crónico e as hormonas do stress, glucocorticoides, são sugeridos como causadores de suscetibilidade neuronal, estando associados a danos na plasticidade cerebral (ex. perda dendrítica/sináptica, neurogénese reduzida), inflamação, bem como a distúrbios neurológicos, como depressão e a doença de Alzheimer (DA); onde o dano da neuroplasticidade é um processo muito importante. Evidências clínicas apoiam uma ligação patológica entre a depressão e a DA, e fundamentos neurobiológicos observados no stress crónico indicam que este pode ser um fator de ligação entre elas. A exposição de modelos animais da DA a stress crónico desencadeiam patologia da proteína Tau, que parece estar relacionada com atrofia e o mau funcionamento neuronal. Tendo como função a regulação do citoesqueleto, a proteína Tau tem um papel importante e inexplorado na remodelação neuroestrutural e nos danos neuroplásticos provocados pelo stress crónico. No primeiro objetivo desta Tese, demonstramos a importância da proteína Tau e o impacto do seu mau funcionamento, causado pelo stress, nos nichos citogénicos do cérebro adulto, com impacto na neurogénese, mas não na astrogliogénese ou oligodendrogénese; pois animais sem a proteína Tau são protegidos contra a supressão neurogénica induzida pelo stress crónico. No segundo objetivo, focamo-nos nas ações do receptor de glucocorticoides (GR) na patologia Tau induzida pelo stress, em tipos celulares específicos. Para isso, geramos murganhos P301LTau com deleção condicional de GR em neurónios ou em microglia. Os resultados mostram que o GR é necessário para a indução de danos cognitivos derivados do stress crónico. O GR neuronal é importante para a precipitação da neuropatologia da Tau bem como para a perda de espinhas apicais na zona CA1 do hipocampo. A deleção de GR na microglia levou à sua reatividade, bem como à perda de espinhas, mas com o stress crónico promoveu a sua génese. A mesma não afetou a agregação/acumulação da proteína Tau. Desta forma, concluímos que os nossos dados apontam para o importante papel do GR neuronal na meadiação da neuropatologia da Tau e identificamos o papel essencial do GR na microglia para a indução de danos cognitivos. Dado que o estilo de vida moderno expõe cada vez mais os indivíduos a altas cargas de stress, é clara a necessidade de compreender melhor a ligação entre o stress crónico e a patogénese da DA, facilitando o tratamento da DA e de outros distúrbios.The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS), University of Minho, Portugal and in the Institute of Biology Paris Seine (IBPS), Sorbonne University, France. Financial Support was provided by a Ph.D. fellowship (PD/BD/127825/2016) from the FCT – Foundation for Science and Technology. This Ph.D. has also been funded by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; and by the projects, NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298; POCI-01-0145-FEDER-007038) supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We acknowledge support from PAULIF, a bilateral “Luso-France Integrated Actions” program and to “France Alzheimer et Maladies Apparentées” program

As ações do stress crónico e dos glucocorticoides na plasticidade cerebral e na patologia da proteína Tau

Cérébrales telles que la dépression ou la maladie d'Alzheimer (MA), car ils favorisent les dommages de la plasticité neuronale, la réactivité gliale, les déficits de l'humeur et les troubles cognitifs. L'exposition de modèles animaux MA à un stress chronique déclenche une pathologie Tau qui est causalement liée à un dysfonctionnement neuronal. Cependant, l'implication de Tau dans les dommages neuroplastiques causés par le stress chronique dans le cerveau adulte reste peu explorée. Dans le premier objectif de ma thèse, nous avons démontré le rôle crucial de Tau et son dysfonctionnement dans les dommages neurogènes induits par le stress, mais pas astrogliogéniques ou oligodendrogènes, dans les niches cytogéniques du cerveau adulte. Dans le deuxième objectif de la thèse, nous avons examiné le rôle du récepteur des glucocorticoïdes (GR) spécifiquement dans les neurones ou la microglie dans la pathologie Tau induite par le stress. Des souris P301LTau ont été générées, dans lesquelles le gène GR est conditionnellement inactivé soit dans les neurones, soit dans la microglie. Nos résultats montrent que GR était nécessaire dans les deux types de cellules pour que le stress chronique induise des déficits cognitifs. De plus, la GR neuronale est importante pour précipiter la neuropathologie Tau et la perte d’épines dendritiques apicales dans la zone hippocampique CA1, tandis que la suppression de la GR microgliale entraîne la perte d’épines dendritiques mais favorise la spinogenèse sous stress sans affecter l'agrégation/accumulation de Tau.Chronic stress and glucocorticoids are implicated in susceptibility to brain pathologies such as depression or Alzheimer’s disease (AD), as they promote neural plasticity damage, glial reactivity, mood deficits and impaired cognition. Exposure of AD animal models to chronic stress triggers Tau pathology that is causally related to neuronal malfunction. However, the precise role of Tau in neuroplastic damage caused by chronic stress in the adult brain remains uncharacterized. In this first objective of my thesis, we demonstrated the crucial role of Tau and its malfunction in stress-driven neurogenic, but not astrogliogenic or oligodendrogenic damage in the cytogenic SGZ and SVZ niches of the adult brain. In the second objective of my thesis we examined the role of glucocorticoid receptor (GR) specifically in neurons or microglia in stress-induced Tau pathology. We generated P301LTau mice in which GR gene is conditionally inactivated either in neurons or in microglia. Our findings show that GR was required in both cell types for chronic stress to induce cognitive deficits. Additionally, neuronal GR is important in precipitating Tau neuropathology and apical spine loss in CA1 hippocampal area, whereas deletion of microglial GR also results in spine loss without any effects on Tau aggregation/accumulation and altered inflammatory gene changes. In conclusion, our data point to an important role of neuronal GR in mediating stress-driven Tau neuropathology and also identifies the essential role of microglial GR in stress-induced cognitive deficits.O stress crónico e as hormonas do stress, glucocorticoides, são sugeridos como causadores de suscetibilidade neuronal, estando associados a danos na plasticidade cerebral (ex. perda dendrítica/sináptica, neurogénese reduzida), inflamação, bem como a distúrbios neurológicos, como depressão e a doença de Alzheimer (DA); onde o dano da neuroplasticidade é um processo muito importante. Evidências clínicas apoiam uma ligação patológica entre a depressão e a DA, e fundamentos neurobiológicos observados no stress crónico indicam que este pode ser um fator de ligação entre elas. A exposição de modelos animais da DA a stress crónico desencadeiam patologia da proteína Tau, que parece estar relacionada com atrofia e o mau funcionamento neuronal. Tendo como função a regulação do citoesqueleto, a proteína Tau tem um papel importante e inexplorado na remodelação neuroestrutural e nos danos neuroplásticos provocados pelo stress crónico. No primeiro objetivo desta Tese, demonstramos a importância da proteína Tau e o impacto do seu mau funcionamento, causado pelo stress, nos nichos citogénicos do cérebro adulto, com impacto na neurogénese, mas não na astrogliogénese ou oligodendrogénese; pois animais sem a proteína Tau são protegidos contra a supressão neurogénica induzida pelo stress crónico. No segundo objetivo, focamo-nos nas ações do receptor de glucocorticoides (GR) na patologia Tau induzida pelo stress, em tipos celulares específicos. Para isso, geramos murganhos P301LTau com deleção condicional de GR em neurónios ou em microglia. Os resultados mostram que o GR é necessário para a indução de danos cognitivos derivados do stress crónico. O GR neuronal é importante para a precipitação da neuropatologia da Tau bem como para a perda de espinhas apicais na zona CA1 do hipocampo. A deleção de GR na microglia levou à sua reatividade, bem como à perda de espinhas, mas com o stress crónico promoveu a sua génese. A mesma não afetou a agregação/acumulação da proteína Tau. Desta forma, concluímos que os nossos dados apontam para o importante papel do GR neuronal na meadiação da neuropatologia da Tau e identificamos o papel essencial do GR na microglia para a indução de danos cognitivos. Dado que o estilo de vida moderno expõe cada vez mais os indivíduos a altas cargas de stress, é clara a necessidade de compreender melhor a ligação entre o stress crónico e a patogénese da DA, facilitando o tratamento da DA e de outros distúrbios

A função da proteína Tau nas alterações induzidas pelo estresse na neurogénese adulta do hipocampo

Dissertação de mestrado em Ciências da SaúdeExposure to chronic stressful conditions is suggested to increase susceptibility to brain pathology as it is associated with neuroplastic deficits as well as impaired cognition and mood. Specifically, structural/functional changes of hippocampal formation are shown to contribute to the pathophysiology of different stress-related disorders, e.g. depression, with particular focus on the dentate gyrus (DG), a region of the hippocampus where stress is shown to suppress neurogenesis in the adult brain. Yet, the underlying cellular mechanisms of the stress-driven neurogenic deficits are poorly understood. Our previous studies show that chronic stress triggers hyperphosphorylation and malfunction of the cytoskeletal protein Tau that leads to neuronal atrophy and memory deficits. In addition, Tau hyperphosphorylation has been causally related to neuronal malfunction and diminished neurogenesis in Alzheimer’s disease. Based on the above findings, we hereby aim to clarify the role of Tau on stressdriven suppression of neurogenesis in adult hippocampal neurogenic niche. For that purpose, we have exposed male Tau knockout animals (Tau-KO) and their wildtype littermates (WT) to nine weeks of a chronic unpredictable stress paradigm and evaluated proliferation, differentiation and survival of newlyborn cells in the adult DG as well as their significance in hippocampus-dependent function using molecular, cellular and behavioral analysis. We found that, while chronic stress decreased proliferating cells in the DG of WT animals, this effect on the above population was not found in Tau-KO animals. Moreover, neuroblasts and newly-born neurons were also found to be reduced in stressed WT, but not in Tau-KO animals, suggesting an essential mediation of Tau in the damage of cell proliferation and neuronal differentiation induced by chronic stress. In contrast, newly-born astrocytes were decreased in both WTs and Tau-KOs after stress exposure, indicating that Tau is not necessary for stress-induced reduction in the DG astrocytic pool. Furthermore, chronic stress reduced cascades known to regulate cell survival and proliferation in the DG such as PI3K/GSK3β /β -catenin pathway followed by concomitant reduction in mTOR signaling in WT, but not Tau-KO. The above findings highlight Tau as a crucial mediator of stress-driven neurogenic deficits in adult hippocampus adding to our mechanistic understanding of the cellular cascades that may convey the pathogenic role of chronic stress in the brain and its plasticity.A exposição ao stress cronico aumenta a susceptibilidade para patologias ligadas ao cérebro e esta associada com alterações de neuroplasticidade e défices cognitivos. O stress-induz alterações estruturais/funcionais no hipocampo contribuindo para o aparecimento de doenças como a depressão, tendo particular foco no giro denteado do hipocampo onde o stress é conhecido como um agente que reduz a neurogénese no cérebro adulto. No entanto, os mecanismos celulares subjacentes ao stressinduz alterações na neurogénese são pouco compreendidos. Os nossos estudos anteriores mostraram que o stress crónico leva a uma hiperfosforilação e a um incorrecto funcionamento da proteína Tau conduzindo a atrofia neuronal e défices de memória. Além disso, a hiperfosforilação da Tau foi relacionada como causa para o mau funcionamento neuronal e diminuição da neurogénese na doença de Alzheimer. Baseado nisto, neste trabalho pretendemos clarificar o papel da Tau no stress-induz redução da neurogénese num nicho neurogénico adulto- o hipocampo. Com esse objectivo, submeteram-se ratinhos macho Tau knockout (Tau-KO) e os suas respectivas ninhadas controle (WT) durante nove semanas ao paradigma de stress crónico imprevisível e avaliou-se a proliferação, diferenciação e sobrevivência das novas células formadas no giro denteado adulto assim como o seu papel em tarefas dependentes do hipocampo usando técnicas de análise molecular, celular e comportamental. Os nossos resultados indicaram que enquanto o stress cronico reduz a proliferação das células no giro denteado dos animais WT, não sendo estes efeitos observados nesta mesma população de células nos animais Tau-KO. Além disso, os neuroblastos e os novos neurónios estão também reduzidos nos animais WT, mas não nos animais Tau-KO, sugerindo um papel mediador da Tau nas alterações da proliferação celular e na diferenciação neuronal induzida pelo stress crónico. Pelo contrário, os novos astrócitos estavam diminuídos em ambos os grupos WT e Tau-KO após exposição a stress, indicando que a proteína Tau não é necessária para o stress-induz redução de astrócitos. Mais ainda, o stress cronico reduz cascatas de sinalização conhecidas por regular a sobrevivência e proliferação celular como PI3K/GSK3β /β -catenin pathway seguido pela concomitante redução na sinalização mTOR nos animais WT, mas não nos Tau-KO, no giro denteado. Estas conclusões destacam o papel crucial da Tau como mediadora do stress-induz défices na neurogénese no hipocampo adulto adicionando conhecimento ao mecanismo das cascatas celulares que podem estar associadas ao papel patológico do stress cronico no cérebro e na sua plasticidade

Adult neurogenic process in the subventricular zone‐olfactory bulb system is regulated by Tau protein under prolonged stress

International audienceObjectives: The area of the subventricular zone (SVZ) in the adult brain exhibits the highest number of proliferative cells, which, together with the olfactory bulb (OB), maintains constant brain plasticity through the generation, migration and integration of newly born neurons. Despite Tau and its malfunction is increasingly related to deficits of adult hippocampal neurogenesis and brain plasticity under pathological conditions [e.g. in Alzheimer's disease (AD)], it remains unknown whether Tau plays a role in the neurogenic process of the SVZ and OB system under conditions of chronic stress, a well-known sculptor of brain and risk factor for AD.Materials and methods: Different types of newly born cells in SVZ and OB were analysed in animals that lack Tau gene (Tau-KO) and their wild-type littermates (WT) under control or chronic stress conditions.Results: We demonstrate that chronic stress reduced the number of proliferating cells and neuroblasts in the SVZ leading to decreased number of newborn neurons in the OB of adult WT, but not Tau-KO, mice. Interestingly, while stress-evoked changes were not detected in OB granular cell layer, Tau-KO exhibited increased number of mature neurons in this layer indicating altered neuronal migration due to Tau loss.Conclusions: Our findings suggest the critical involvement of Tau in the neurogenesis suppression of SVZ and OB neurogenic niche under stressful conditions highlighting the role of Tau protein as an essential regulator of stress-driven plasticity deficits

Chronic stress triggers divergent dendritic alterations in immature neurons of the adult hippocampus, depending on their ultimate terminal fields

Chronic stress, a suggested precipitant of brain pathologies, such as depression and Alzheimer's disease, is known to impact on brain plasticity by causing neuronal remodeling as well as neurogenesis suppression in the adult hippocampus. Although many studies show that stressful conditions reduce the number of newborn neurons in the adult dentate gyrus (DG), little is known about whether and how stress impacts on dendritic development and structural maturation of these newborn neurons. We, herein, demonstrate that chronic stress impacts differentially on doublecortin (DCX)-positive immature neurons in distinct phases of maturation. Specifically, the density of the DCX-positive immature neurons whose dendritic tree reaches the inner molecular layer (IML) of DG is reduced in stressed animals, whereas their dendritic complexity is increased. On the contrary, no change on the density of DCX-positive neurons whose dendritic tree extends to the medial/outer molecular layer (M/OML) of the DG is found under stress conditions, whereas the dendritic complexity of these cells is diminished. In addition, DCX+ cells displayed a more complex and longer arbor in the dendritic compartments located in the granular cell layer of the DG under stress conditions; on the contrary, their dendritic segments localized into the M/OML were shorter and less complex. These findings suggest that the neuroplastic effects of chronic stress on dendritic maturation and complexity of DCX+ immature neurons vary based on the different maturation stage of DCX-positive cells and the different DG sublayer, highlighting the complex and dynamic stress-driven neuroplasticity of immature neurons in the adult hippocampus.Portuguese Foundation for Science and Technology (FCT) Investigator grants (IF/01799/2013 and IF/01079/2014, respectively). C.D. is a recipient of PhD fellowship of PhDOC program. P.P. and E.F. hold FCT post-doc fellowships. This work was funded by FCT research grants “PTDC/SAU-NMC/113934/2009” (to I.S.), the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013), and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER

Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity

Type 2 diabetes increases the risk for dementia, including Alzheimer's disease (AD). Pioglitazone (Pio), a pharmacological agonist of the peroxisome proliferator-activated receptor γ (PPARγ), improves insulin sensitivity and has been suggested to have potential in the management of AD symptoms, albeit through mostly unknown mechanisms. We here investigated the potential of Pio to counter synaptic malfunction and loss, a characteristic of AD pathology and its accompanying cognitive deficits. Results from experiments on primary mouse neuronal cultures and a human neural cell line (SH-SY5Y) show that Pio treatment attenuates amyloid β (Aβ)-triggered the pathological (mis-) processing of amyloid precursor protein (APP) and inhibits Aβ-induced accumulation and hyperphosphorylation of Tau. These events are accompanied by increased glutamatergic receptor 2B subunit (GluN2B) levels that are causally linked with neuronal death. Further, Pio treatment blocks Aβ-triggered missorting of hyperphosphorylated Tau to synapses and the subsequent loss of PSD95-positive synapses. These latter effects of Pio are PPARγ-mediated since they are blocked in the presence of GW9662, a selective PPARγ inhibitor. Collectively, these data show that activated PPARγ buffer neurons against APP misprocessing, Tau hyperphosphorylation and its missorting to synapses and subsequently, synaptic loss. These first insights into the mechanisms through which PPARγ influences synaptic loss make a case for further exploration of the potential usefulness of PPARγ agonists in the prevention and treatment of synaptic pathology in AD.SwitchBox Project, funded by the European Union (FP7-Health, Contract 259772) to OA, and by grants from the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013), the European Regional Development Fund COMPETE (FCOMP-01-0124- FEDER-037298), Project NORTE-01-0145-FEDER-000013 (Portugal 2020 Partnership Agreement, European Regional Development Fund), FEDER funds from Competitiveness Factors Operational Programme (COMPETE), and grants from the Portuguese Foundation for Science and Technology (FCT) to IS (POCI-01-0145-FEDER-007038) and to PG (PD/BD/135271/2017). The funding agencies played no role in the design, execution or interpretation of the findings reported herein. SM was partly supported by a pre-doctoral fellowship from the Max Planck Society and received a Short-Term Scientific Mission bursary from COST Action MouseAge (BM1402