The Role of Inflammation in Amyloid Diseases

Amyloid diseases are characterized by the abnormal accumulation of proteinaceous aggregates (amyloid fibrils or plaques) in tissues and organs. This class of diseases is also characterized by the presence of inflammation. Amyloid fibrils arise from the partial denaturing and unfolding of native proteins. The accumulation of amyloid fibrils causes tissue damage and elicits local and nonlocal immune cell infiltration into tissue and proinflammatory cytokine production. Moreover, these conditions fuel a vicious cycle that can increase amyloid production and create an environment of chronic inflammation. A chronically inflamed tissue rapidly deteriorates and loses its function. In this chapter, we will discuss important data gathered over the years describing the role of inflammation in amyloid diseases. We will describe how inflammation begins and how it affects disease progression for major amyloid diseases, such as Alzheimer’s disease (AD) and hereditary TTR amyloidosis (hATTR). Lastly, we will discuss the recent advancements in treatments for amyloid diseases and how they address inflammation in affected patients

Dissecting the structure, thermodynamic stability, and aggregation properties of the A25T transthyretin (A25T-TTR) variant involved in leptomeningeal amyloidosis: identifying protein partners that co-aggregate during A25T-TTR fibrillogenesis in cerebrospinal fluid

Deposition of amorphous aggregates and fibrils of transthyretin (TTR) in leptomeninges and subarachnoid vessels is a characteristic of leptomeningeal amyloidosis (LA), a currently untreatable cerebral angiopathy. Herein, we report the X-ray structure of the A25T homotetramer of TTR, a natural mutant described in a patient with LA. The structure of A25T-TTR is indistinguishable from that of wild-type TTR (wt-TTR), indicating that the difference in amyloidogenicity between A25T-TTR and wt-TTR cannot be ascribed to gross structural differences. Using pressure-induced dissociation of the tetramer, we show that A25T-TTR is 3 kcal/mol less stable than L55P-TTR, the most aggressive mutant of TTR described to date. After incubation for 15 days at 37 °C (pH 7.3), A25T-TTR forms mature amyloid fibrils. To mimic the environment in which TTR aggregates, we investigated aggregation in cerebrospinal fluid (CSF). Unlike L55P-TTR, A25T-TTR rapidly forms amyloid aggregates in CSF that incorporated several protein partners. Utilizing a proteomics methodology, we identified 19 proteins that copurified with A25T-TTR amyloid fibrils. We confirmed the presence of proteins previously identified to be associated with TTR aggregates in biopsies of TTR amyloidosis patients, such as clusterin, apolipoprotein E, and complement proteins. Moreover, we identified novel proteins, such as blood coagulation proteins. Overall, our results revealed the in vitro characterization of TTR aggregation in a biologically relevant environment, opening new avenues of investigation into the molecular mechanisms of LA.CNPqFAPERJCAPE

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development.

Microglial cells play a key role in brain homeostasis from development to adulthood. Here we show the involvement of a site-specific phosphorylation of Presenilin 1 (PS1) in microglial development. Profiles of microglia-specific transcripts in different temporal stages of development, combined with multiple systematic transcriptomic analysis and quantitative determination of microglia progenitors, indicate that the phosphorylation of PS1 at serine 367 is involved in the temporal dynamics of microglial development, specifically in the developing brain rudiment during embryonic microgliogenesis. We constructed a developing brain-specific microglial network to identify transcription factors linked to PS1 during development. Our data showed that PS1 functional connections appear through interaction hubs at Pu.1, Irf8 and Rela-p65 transcription factors. Finally, we showed that the total number of microglia progenitors was markedly reduced in the developing brain rudiment of embryos lacking PS1 phosphorylation compared to WT. Our work identifies a novel role for PS1 in microglial development

Massoterapia para a Terceira Idade

MASSOTERAPIA PARA A TERCEIRA IDADE*SALOMÃO, L do C.A.1, SILVA, R.C.L. da.1, AZEVEDO, J.F. 1, SILVA, L.L. da.2, & GUTIÉRREZ, I.E.M. de.4 1-       Discente de Enfermagem, Departamento de Saúde – UEFS, Bolsista PIBEX.2-       Discente de Enfermagem, Departamento de Saúde – UEFS, Voluntária PIBEX.3-      Professora Orientadora, Departamento de Saúde – UEFS.*Programa de Extensão Terapias não Convencionais (TnC) e Você (RESOLUÇÃO CONSEPE n° 72/2013) IntroduçãoA expectativa de vida da população brasileira vem cada vez mais aumentando, o último censo demográfico realizado pelo Instituto Brasileiro de Geografia e Estatística (IBGE), em 2018 indicou 79,9 anos para mulheres e 72,8 anos para homens. Atualmente o Brasil tem 28 milhões de pessoas com idade igual ou superior a 60 anos, representando um percentual de 13% da população, e segundo projeções do IBGE esse percentual dobrará nas próximas décadas (IBGE, 2018).No cenário atual de avanços na saúde pública, o envelhecimento populacional é inevitável, e traz consigo preocupações diversas, com o bem-estar do indivíduo, a saúde e seus direitos no geral (BELASCO; OKUNO, 2019). Com a chegada da terceira idade, o corpo humano sofre constantes mudanças fisiológicas que podem fragilizar a saúde e o bem-estar da pessoa idosa, tornando necessário algumas intervenções, visando proporcionar um envelhecimento sadio e livre de dependência.   Sabe-se que envelhecer perpassa por constantes transformações, as quais repercutem no bem-estar físico, psíquico e social, e que há certa repulsa e dificuldade para a pessoa se adaptar às mudanças (MINAYO; FIRMO, 2019). Esses fatores podem ser responsáveis por distanciar a pessoa idosa de políticas públicas que promovam seus direitos institucionais, favorecendo assim o envelhecimento precário e desassistido (MONTEIRO, 2019). Levando em conta que a saúde é direito de todos e dever do estado, em 2006 o SUS incorporou aos seus métodos de cuidados, as Práticas Integrativas e Complementares (PIC) (BRASIL, 2015), que detém de métodos não convencionais popularmente conhecidos e menos invasivos que os métodos convencionais de cuidados à saúde.A massagem relaxante é uma PIC que se emprega movimentos firmes e suaves sobre o corpo para promover alívio das dores musculares, do estresse (devido à liberação de hormônios como a serotonina e a ocitocina), bem como melhora na circulação sanguínea, disposição, humor, dentre outros benefícios (BRASIL, 2018). Trata-se uma terapia milenar, cuja prática é realizada a 1500 a. C pelos chineses e tornou-se mundialmente conhecida por seus efeitos terapêuticos durante a Idade Média ao ser disseminada por gregos, romanos, indianos e japoneses (CASSAR, 2001).O ato de empregar técnicas de massagem sob segmentos musculares do corpo promove manifestações de origem não apenas fisiológica, mas também de ordem psíquica, química e mecânica sob o indivíduo. Além dos demais benefícios, a massoterapia pode reduzir ou atrasar alguns efeitos comuns da terceira idade, como déficit de locomoção e capacidade física diminuída (NESSI, 2018). Sendo assim, o Programa de Extensão Terapias não Convencionais (TnC) e Você da UEFS (RE CONSEPE nº 72/2013) reconhece a importância de ofertar massoterapia aos idosos cadastrados do Programa de Extensão Universidade Aberta a Terceira Idade (UATI) (RE CONSEPE nº 13/1992).Palavras-chave: massagem relaxante, idoso, PICS, bem-estar.Material e Métodos  As sessões de massoterapia ocorreram uma vez por semana no Laboratório de Enfermagem (Labenf), para um total de 64 idosos cadastrados na oficina de Massagem relaxante da UATI em 2019. As massagens ocorreram em macas, com auxílio de instrumentos massageadores e música relaxante, cada sessão com uma duração média de 30 minutos. Eram feitos o controle de sinais vitais, como pressão arterial e contagem do pulso, também eram mensurados o nível de dor e estresse antes e após cada sessão para registro nos formulários de acompanhamento. Havendo uma média de quatro discentes por turno nos atendimentos.ResultadosPode-se observar que os idosos que procuravam as sessões de massoterapia praticavam outras atividades de recreação na Universidade e relacionavam a massoterapia com momento de lazer, descanso e relaxamento, também foi possível identificar alguns hipertensos que faziam uso contínuo de anti-hipertensivos e permaneciam com a pressão arterial descontrolada, necessitando das devidas orientações quanto ao estilo de vida saudável, benefícios das PICS e a importância de fazer acompanhamento com equipe multiprofissional de saúde, inclusive geriatras.A massagem proporcionou aos idosos cuidados alternativos com a saúde e permitiu que eles fossem assistidos semanalmente, mudassem alguns hábitos que estavam impactando negativamente na saúde e prevenindo futuros danos à mesma. Foi observado por meio dos relatos dos idosos e de dados de formulários que os benefícios obtidos condiziam com o que estava previsto nas literaturas consultadas que falavam em aumento da circulação sanguínea, alívio de dores musculares e estresse, melhoras do humor, dentre outros, mas também pudemos notar que para o idoso se trata também de um momento de terapia, onde se sentem a vontade para relatar suas angústias e sentirem-se acolhidos pelos discentes que os atendem.Considerações FinaisA prática da massagem para a comunidade acadêmica ajuda a desmistificar a busca pela massagem como sendo algo supérfluo, luxuoso, meramente estético, ou apenas para classes sociais altas e atletas, já que a massagem pode ser ofertada no SUS para seus usuários. Ações como as práticas de massoterapia são importantes para a terceira idade, pois atuam na promoção da saúde e prevenção de doenças variadas. A massoterapia proporcionou saúde ao idoso em seu âmbito físico, biológico e psíquico, auxiliando a amenizar os efeitos do envelhecimento e favorecendo bem-estar, dessa forma quanto mais a população e profissionais estiverem cientes de seus benefícios, maior visibilidade terão as PICS frente aos profissionais inseridos no SUS e nas instituições de ensino

Correction: Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development.

[This corrects the article DOI: 10.1371/journal.pone.0237773.]

Presenilin 1 phosphorylation regulates amyloid-β degradation by microglia

Amyloid-β peptide (Aβ) accumulation in the brain is a hallmark of Alzheimer’s Disease. An important mechanism of Aβ clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aβ. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aβ oligomers due to a phagolysosome dysfunction. An Alzheimer’s mouse model containing phospho-deficient PS1 show severe Aβ accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer’s -associated phenotypes

Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation

Abstract Background Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. Methods Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. Results Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. Conclusions Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments

Dissecting the Structure, Thermodynamic Stability, and Aggregation Properties of the A25T Transthyretin (A25T-TTR) Variant Involved in Leptomeningeal Amyloidosis: Identifying Protein Partners That Co-Aggregate during A25T-TTR Fibrillogenesis in Cerebrospinal Fluid

Deposition of amorphous aggregates and fibrils of transthyretin (TTR) in leptomeninges and subarachnoid vessels is a characteristic of leptomeningeal amyloidosis (LA), a currently untreatable cerebral angiopathy. Herein, we report the X-ray structure of the A25T homotetramer of TTR, a natural mutant described in a patient with LA. The structure of A25T-TTR is indistinguishable from that of wild-type TTR (wt-TTR), indicating that the difference in amyloidogenicity between A25T-TTR and wt-TTR cannot be ascribed to gross structural differences. Using pressure-induced dissociation of the tetramer, we show that A25T-TTR is 3 kcal/mol less stable than L55P-TTR, the most aggressive mutant of TTR described to date. After incubation for 15 days at 37 °C (pH 7.3), A25T-TTR forms mature amyloid fibrils. To mimic the environment in which TTR aggregates, we investigated aggregation in cerebrospinal fluid (CSF). Unlike L55P-TTR, A25T-TTR rapidly forms amyloid aggregates in CSF that incorporated several protein partners. Utilizing a proteomics methodology, we identified 19 proteins that copurified with A25T-TTR amyloid fibrils. We confirmed the presence of proteins previously identified to be associated with TTR aggregates in biopsies of TTR amyloidosis patients, such as clusterin, apolipoprotein E, and complement proteins. Moreover, we identified novel proteins, such as blood coagulation proteins. Overall, our results revealed the in vitro characterization of TTR aggregation in a biologically relevant environment, opening new avenues of investigation into the molecular mechanisms of LA