Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease.

Early Alzheimer's disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions

Alguns contributos das Neurociências para a Educação: Os ambientes enriquecidos aumentam a capacidade de aprendizagem do nosso cérebro?

The reflection and discussion on the role of genetic specification and experience in the acquisition of a function and in the development of an individual reflects a fascinating and very current debate among those working in the area of behavior and development. Concerning the development of human behavior and the influence of biological heritage and the envitonment, conflicting and sometimes exclusive positions were established. On the one hand, adherents of genetic inheritance exclude the possibility of the influence of the environment. On the other hand, supporters of the environment exclude genetic inheritance. There is also an eclectic position, reconciling both extremes. Furthermore, within the scope of the trends themselves, differentiating nuances emerge. It is therefore, a very controversial subject to which we dedicate this work from a Neuroscience perspective. We will approach brain neuroplasticity as the ability of the nervous system to change and adapt, in response to internal and external stimuli, including structural and / or functional changes throughout life. Brain plasticity is one of the pillars of learning and memory processes. In short, the role of Neurosciences in the field of Educational Sciences is taking shape and the concept of neuroplasticity is a sine qua non condition for trying to establish a connection between education, behavior and the brain.A reflexão e a discussão sobre o papel da especificação genética e da experiência na aquisição de uma função e no desenvolvimento de um indivíduo traduz um debate fascinante e muito atual entre quem trabalha na área do desenvolvimento do comportamento. Acerca do desenvolvimento do comportamento humano e da influência da herança biológica e do meio ambiente estabeleceram-se posições desencontradas e, por vezes, exclusivistas. De um lado, os adeptos da herança genética excluem a possibilidade da influência do meio ambiente. Do outro lado, os adeptos do meio ambiente excluem a herança genética. Existe também uma posição eclética, conciliando ambos os extremos. Além disso, no âmbito das próprias tendências surgem matizes diferenciadoras. Trata-se, portanto, de um assunto bastante polémico ao qual dedicamos este trabalho numa perspetiva das Neurociências. Abordaremos a neuroplasticidade cerebral como a capacidade que o sistema nervoso possui de mudar e adaptar-se, em resposta a estímulos internos e externos, induzindo alterações estruturais e / ou funcionais, ao longo da vida. A plasticidade cerebral constitui um dos pilares dos processos de aprendizagem e de memória. Quando se aprende e se memoriza ou quando se descobre algo desconhecido, a nova experiência deixa uma marca que se traduz em alterações no cérebro. Em suma, o papel das Neurociências no domínio das Ciências da Educação vai ganhando corpo e o conceito de neuroplasticidade é uma condição sine qua non para se tentar estabelecer uma ligação entre a educação, o comportamento e o cérebro

A importância do equilíbrio entre flexibilidade e estabilidade neuronal na formação de memórias

The neurobiological mechanisms behind memory formation remain unknown. Synapses are essential neuronal sub-compartments for the transmission of information within neuronal networks. Hebbian and homeostatic plasticity mechanisms, are two types of processes that play a role on synaptic modifications during the formation of memories. The interaction between these types of plasticity controls the balance between neuronal flexibility and stability to keep neuronal activity within a physiological window. Thus, it is important to better understand these mechanisms and identify the basic units of this system as they may be involved in the onset of neurological disorders. Here, I shed light on the impact of these mechanisms in the early phase of Alzheimer’s disease.Os mecanismos neurobiológicos essenciais para a formação de memórias são ainda pouco compreendidos. No entanto, sabe-se que as sinapses, sub-compartimentos neuronais essenciais para a transmissão de informação nas redes neuronais, são elementos imprescindíveis para este processo. Diferentes formas de plasticidade (hebbiano e homeostáticos) estão na base de modificações sinápticas que acontecem durante a formação de memórias. A interação destes mecanismos controlam o equilíbrio entre a flexibilidade e a estabilidade neuronal mantendo assim a sua actividade dentro de uma janela fisiológica. É, portanto, necessário conhecer melhor estes mecanismos de plasticidade e assim identificar que tipo de alterações nas unidades básicas deste sistema podem estar na origem de distúrbios do funcionamento do cérebro. Neste artigo, reflito sobre a potencial implicação destas alterações nas fases iniciais da doença de Alzheimer

Tauopathy seeding models as a platform for Tau aggregation and clearance study

Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de CoimbraA doença de Alzheimer é a forma de demência mais prevalente. Quando a proteína Tau perde a conformação correcta forma agregados, começando por originar oligomeros e mais tarde fibrilas de grandes dimensões dando origem a trancas neurofibrilares. Alguns estudos sugerem que estas espécies são transmitidas através das áreas do cérebro danificando o circuito neuronal. Para parar o avanço da doença muitos trabalhos têm em foco o desenvolvimento de terapias que manipulam a fosforilação desta proteína, a estabilização dos microtubulos e a indução da degradação da Tau. Para desenvolver terapias que impedem a agregação ou que induzam a degradação da Tau, é necessário desenvolver modelos que recapitulam a agregação. Neste trabalho “seeding effect” foi a estratégia utilizada para induzir a agregação da hTauP301L. No presente trabalho dois modelos in vitro baseados nesta estratégia foram utilizados – um desenvolvido em linhas celulares e outro em culturas neuronais primarias – onde se observou a hiper-fosforilação e agregação da Tau. A co-expressão da GSK3β aumentou a fosforilacao na ser202/thr205 na Tau solúvel e insolúvel, mas apenas a sua expressão não foi suficiente para induzir agregação. Em culturas neuronais primárias a fosforilação e agregação da Tau aumentam ao longo do tempo. A inibição da Hsp90 reduziu os níveis de Tau totais de e fosforilados no epitopo AT8, dando importância a esta estratégia como um potencial mecanismo para degradação da Tau.Com este trabalho produzimos dois modelos onde estudos em nucleação, agregação e transmissão sináptica da Tau poderão ser feitos. Estes modelos são ferramentas válidas para o desenvolvimento de fármacos para AD e outras TauopatiasAlzheimer Disease is the most prevalent dementia. Abnormal folding of Tau leads to generation of aggregated Tau species like oligomers and further NFTs. Toxic Tau species were suggested to spread trough human brain and damage the neuronal circuit. To halt disease progression a noteworthy development in therapies based on phosphorylation modulation, Microtubule stabilization and enchantment of Tau clearance have been done. To develop therapies against Tau aggregation and aggregates clearance, the build up of models that recapitulates Tau pathology are required. In the following work the “seeding” strategy was used to achieve aggregation of hTauP301L. We worked with two in-vitro seeding models – cellular and primary neuronal- where phosphorylated insoluble hTauP301L is present. GSK3β was shown to increase ser202/thr205 phosphorylation in soluble and insoluble hTauP301L expressed in QBI but was not sufficient to induce aggregation alone. In primary neuronal seeding model tau aggregation and phosphorylation was increased over-time. Hsp90 inhibition was found to reduce total and AT8 immuno-reactive hTauP301L levels, emerging as a potential drug for Tau clearance. With this work we provide two models to study the mechanisms behind tau nucleation, aggregation, and trans-synaptic spreading. These models are valuable tools for the development of drugs for AD and Tauopathies

Modulation of tau pathology propagation

Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of Tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation which can have implications for "synaptic repair" therapies which may turn out to have adverse effects by promoting propagation of Tau pathology. Mechanisms underlying the release and internalization of Tau aggregates are unclear. Some evidences suggest that internalization step relies on endocytic mechanisms. BIN1 is a late-onset AD risk factor involved in endocytosis and membrane trafficking. Therefore we investigated if myc box-dependent-interacting protein 1 (BIN1) influences endocytosis and modulates Tau pathology propagation. We first found a link between BIN1 levels and Tau pathology propagation. BIN1 levels inversely correlated with Tau pathology propagation in two in vitro models. We further analysed the biological role of this protein and found that changes in BIN1 neuronal levels profoundly impairs endocytic flux. Moreover our work suggests that the involvement of BIN1 in Tau pathology propagation is by mediating the endocytosis of Tau aggregates. We show that when Tau aggregates hijack endocytic routes induce membrane damaging, suggesting that they escape from endocytic compartments to the cytosol. Taken together our work suggests that modulating endocytic flux, through BIN1 levels, halts or enhances Tau aggregates uptake and further Tau pathology propagation between cellsstatus: publishe

Loss of Bin1 Promotes the Propagation of Tau Pathology

Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer’s disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking

Loss of Bin1 Promotes the Propagation of Tau Pathology

Tau pathology propagates within synaptically connected neuronal circuits, but the underlying mechanisms are unclear. BIN1-amphiphysin2 is the second most prevalent genetic risk factor for late-onset Alzheimer's disease. In diseased brains, the BIN1-amphiphysin2 neuronal isoform is downregulated. Here, we show that lowering BIN1-amphiphysin2 levels in neurons promotes Tau pathology propagation whereas overexpression of neuronal BIN1-amphiphysin2 inhibits the process in two in vitro models. Increased Tau propagation is caused by increased endocytosis, given our finding that BIN1-amphiphysin2 negatively regulates endocytic flux. Furthermore, blocking endocytosis by inhibiting dynamin also reduces Tau pathology propagation. Using a galectin-3-binding assay, we show that internalized Tau aggregates damage the endosomal membrane, allowing internalized aggregates to leak into the cytoplasm to propagate pathology. Our work indicates that lower BIN1 levels promote the propagation of Tau pathology by efficiently increasing aggregate internalization by endocytosis and endosomal trafficking.publisher: Elsevier articletitle: Loss of Bin1 Promotes the Propagation of Tau Pathology journaltitle: Cell Reports articlelink: http://dx.doi.org/10.1016/j.celrep.2016.09.063 content_type: article copyright: © 2016 The Authors.status: publishe

Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology

Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer's disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.publisher: Elsevier articletitle: Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation journaltitle: Cell Reports articlelink: http://dx.doi.org/10.1016/j.celrep.2015.04.043 content_type: article copyright: Copyright © 2015 The Authors. Published by Elsevier Inc.status: publishe