The role of TAU protein in the pathophysiology of frontotemporal dementia

CONTEXTO: Sob a denominação demência frontotemporal (DFT) enquadram-se importantes síndromes demenciais de natureza degenerativa progressiva que acometem os lobos frontais e temporais em ambos os hemisférios. As DFTs podem ser agrupadas, segundo seus aspectos clínicos dominantes, em variante frontal, afasia progressiva não fluente e demência semântica. A proteína Tau tem papel importante na patogenia desses transtornos, e anormalidades conformacionais estão presentes em até 50% dos casos de DFT esporádica. Do ponto de vista neuropatológico, as DFTs podem ser classificadas em Tau negativas e Tau positivas, estas últimas também classificadas entre as tauopatias. OBJETIVO: Neste trabalho será revisto o papel da proteína Tau na patogenia das DFTs. MÉTODOS: Busca simples no Scielo e na Pubmed por meio das palavras-chave: "tauopatias", "demência frontotemporal" e "proteína Tau". Foram revisados os artigos publicados a partir de 2000, e artigos anteriores de maior relevância, identificados a partir das referências estudadas. RESULTADOS: Dentre os trabalhos incluídos nesta análise, 12 abordam as tauopatias, sendo dez originais e sete de revisão. Foram identificados 20 artigos sobre DFT, sendo 16 artigos originais e quatro de revisão. CONCLUSÃO: A proteína Tau tem papel fundamental na patogenia das DFTs e outras doenças neurodegenerativas. O conhecimento desses mecanismos fisiopatológicos é o passo inicial para o desenvolvimento de estratégias terapêuticas.BACKGROUND: Frontotemporal dementia (FTD) represents an important group of neurodegenerative diseases, affecting temporal and frontal lobes of both hemispheres. FTD can be divided into three clinical subsyndromes: frontal variant, non-fluent progressive aphasia, and semantic dementia. Abnormalities of the metabolism of Tau protein are present in the physiopathology of FTD, and is found in approximately 50% of sporadic cases, supporting the classification of the FTDs into Tau-negative and Tau-positive subtypes, the latter also called "Tauopathies". OBJECTIVE: To review the role of Tau in the pathophysiology of FTD. METHODS: Review of the literature on FTD published in the Pubmed and Scielo databases since the year 2000, using the keywords: Tau, Tauopathies, frontotemporal dementia. Relevant references previously published, as indicated in the reference list of selected articles, were also included. RESULTS: Through electronic search we identified 12 articles addressing Tauopathies (ten containing original data and seven reviews), and 20 articles (16 with original data and four reviews) on FTDs. CONCLUSIONS: There is consistent evidence in the literature to support the notion that Tau protein plays a crucial role in the pathogenesis of FTDs and other neurodegenerative dementias, and the knowledge on these mechanisms is necessary for the development of more specific therapies

Papel da proteína Tau na fisiopatologia da demência frontotemporal

BACKGROUND: Frontotemporal dementia (FTD) represents an important group of neurodegenerative diseases, affecting temporal and frontal lobes of both hemispheres. FTD can be divided into three clinical subsyndromes: frontal variant, non-fluent progressive aphasia, and semantic dementia. Abnormalities of the metabolism of Tau protein are present in the physiopathology of FTD, and is found in approximately 50% of sporadic cases, supporting the classification of the FTDs into Tau-negative and Tau-positive subtypes, the latter also called "Tauopathies". OBJECTIVE: To review the role of Tau in the pathophysiology of FTD. METHODS: Review of the literature on FTD published in the Pubmed and Scielo databases since the year 2000, using the keywords: Tau, Tauopathies, frontotemporal dementia. Relevant references previously published, as indicated in the reference list of selected articles, were also included. RESULTS: Through electronic search we identified 12 articles addressing Tauopathies (ten containing original data and seven reviews), and 20 articles (16 with original data and four reviews) on FTDs. CONCLUSIONS: There is consistent evidence in the literature to support the notion that Tau protein plays a crucial role in the pathogenesis of FTDs and other neurodegenerative dementias, and the knowledge on these mechanisms is necessary for the development of more specific therapies.CONTEXTO: Sob a denominação demência frontotemporal (DFT) enquadram-se importantes síndromes demenciais de natureza degenerativa progressiva que acometem os lobos frontais e temporais em ambos os hemisférios. As DFTs podem ser agrupadas, segundo seus aspectos clínicos dominantes, em variante frontal, afasia progressiva não fluente e demência semântica. A proteína Tau tem papel importante na patogenia desses transtornos, e anormalidades conformacionais estão presentes em até 50% dos casos de DFT esporádica. Do ponto de vista neuropatológico, as DFTs podem ser classificadas em Tau negativas e Tau positivas, estas últimas também classificadas entre as tauopatias. OBJETIVO: Neste trabalho será revisto o papel da proteína Tau na patogenia das DFTs. MÉTODOS: Busca simples no Scielo e na Pubmed por meio das palavras-chave: "tauopatias", "demência frontotemporal" e "proteína Tau". Foram revisados os artigos publicados a partir de 2000, e artigos anteriores de maior relevância, identificados a partir das referências estudadas. RESULTADOS: Dentre os trabalhos incluídos nesta análise, 12 abordam as tauopatias, sendo dez originais e sete de revisão. Foram identificados 20 artigos sobre DFT, sendo 16 artigos originais e quatro de revisão. CONCLUSÃO: A proteína Tau tem papel fundamental na patogenia das DFTs e outras doenças neurodegenerativas. O conhecimento desses mecanismos fisiopatológicos é o passo inicial para o desenvolvimento de estratégias terapêuticas

Analysis of genetic susceptibility to mercury contamination evaluated through molecular biomarkers in at-risk amazon amerindian populations

We investigated Individual differences in susceptibility to methylmercury (MeHg) contamination and its relationship with polymorphisms of the detoxifying enzyme glutathione S-transferase (GST). In Brazil, some Amerindian tribes from the Amazon region have an increased level of mercury in their hair. Samples of hair and blood were taken from inhabitants of two villages in the Kayabi and Munduruku Amerindian communities to investigate mercury levels in association with genetic polymorphism of GSTs. Other molecular biological markers were also studied, such as hemoglobin, haptoglobin and glucose 6-phosphate dehydrogenase (G-6-PDH). Higher levels of mercury contamination were found in the Kayabi villagers, who had a null genotype (GSTM1 0/0, also denominated GSTM1 null) frequency of 26%, than in the Munduruku villagers, for which the null genotype frequency was 0%. Individuals with the GSTM1 null phenotype had higher concentrations of mercury in their hair than individuals with GSTM1+/+ phenotypes (F = 21.51, p < 0.0001). No association with other markers studied was observed. This study suggests that GSTM1 may be involved in the biotransformation of mercury in humans

Development and evaluations of the ancestry informative markers of the VISAGE Enhanced Tool for Appearance and Ancestry

The VISAGE Enhanced Tool for Appearance and Ancestry (ET) has been designed to combine markers for the prediction of bio-geographical ancestry plus a range of externally visible characteristics into a single massively parallel sequencing (MPS) assay. We describe the development of the ancestry panel markers used in ET, and the enhanced analyses they provide compared to previous MPS-based forensic ancestry assays. As well as established autosomal single nucleotide polymorphisms (SNPs) that differentiate sub-Saharan African, European, East Asian, South Asian, Native American, and Oceanian populations, ET includes autosomal SNPs able to efficiently differentiate populations from Middle East regions [...]The study was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 740580 within the framework of the VISible Attributes through GEnomics (VISAGE) Project and Consortium. M.d.l.P. is supported by a post-doctorate grant funded by the Consellería de Cultura, Educación e Ordenación Universitaria e da Consellería de Economía, Emprego e Industria from Xunta de Galicia, Spain (ED481D-2021–008). J.R. is supported by the “Programa de axudas á etapa predoutoral” funded by the Consellería de Cultura, Educación e Ordenación Universitaria e da Consellería de Economía, Emprego e Industria from Xunta de Galicia, Spain (ED481A-2020/039). C.P., A.F.A., A.M.M., M.d.l.P., M.V.L. and the work to compile ancestry informative tri-allelic SNPs and microhaplotypes are supported by MAPA, ‘Multiple Allele Polymorphism Analysis’ (BIO2016–78525-R), a research project funded by the Spanish Research State Agency (AEI) and co-financed with ERDF funds. The population studies by S.O. at University of Santiago de Compostela, were financed by the Fundação de Apoio a Pesquisa do Distrito Federal (FAPDF), BrazilS

Design, synthesis, and biological evaluation of new thalidomide–donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation

A new series of eight multifunctional thalidomide–donepezil hybrids were synthesized based on the multi target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline 1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 μM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE–donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1β levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood–brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1β. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide–donepezil-based hybrid molecular architectur

Short-Term Withdrawal of Mitogens Prior to Plating Increases Neuronal Differentiation of Human Neural Precursor Cells

Background: Human neural precursor cells (hNPC) are candidates for neural transplantation in a wide range of neurological disorders. Recently, much work has been done to determine how the environment for NPC culture in vitro may alter their plasticity. Epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) are used to expand NPC; however, it is not clear if continuous exposure to mitogens may abrogate their subsequent differentiation. Here we evaluated if short-term removal of FGF-2 and EGF prior to plating may improve hNPC differentiation into neurons.Principal Findings: We demonstrate that culture of neurospheres in suspension for 2 weeks without EGF-FGF-2 significantly increases neuronal differentiation and neurite extension when compared to cells cultured using standard protocols. in this condition, neurons were preferentially located in the core of the neurospheres instead of the shell. Moreover, after plating, neurons presented radial rather than randomly oriented and longer processes than controls, comprised mostly by neurons with short processes. These changes were followed by alterations in the expression of genes related to cell survival.Conclusions: These results show that EGF and FGF-2 removal affects NPC fate and plasticity. Taking into account that a three dimensional structure is essential for NPC differentiation, here we evaluated, for the first time, the effects of growth factors removal in whole neurospheres rather than in plated cell culture.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Institutos do Milenio de Bioengenharia TecidualUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilUniv Fed Rio de Janeiro, Inst Ciencias Biomed, BR-21941 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilFAPESP: fellowCNPq: fellowWeb of Scienc

Vulnerabilidades ao HIV/aids no Contexto Brasileiro: iniquidades de gênero, raça e geração

OBJETIVO: Analisar o conhecimento da população sobre DST/aids, bem como os discursos sobre o uso do preservativo e das práticas sexuais. MÉTODOS: Pesquisa qualitativa com 64 indivíduos jovens e adultos, brancos e negros, sexualmente ativos, de ambos os sexos. A vulnerabilidade ao HIV/aids foi discutida a partir da perspectiva racial (negros ou brancos), geracional (entre 16 e 24 anos ou 45 e mais) e de gênero (masculino ou feminino). Foram realizadas entrevistas em profundidade com roteiro semiestruturado nas cidades de São Paulo (SP) e Recife (PE), sobre os temas: conhecimento e percepção sobre DST/aids, percepção de risco individual, negociação e uso de preservativos, iniciação sexual e práticas sexuais. RESULTADOS: Os indivíduos menos escolarizados, os homens, os mais velhos e os moradores de Recife foram os menos informados sobre DST/aids. Pessoas acima de 45 anos e os menos escolarizados possuíam conhecimento incipiente sobre as formas de transmissão e prevenção das DST/aids. O uso do preservativo entre os entrevistados de ambas as cidades foi relativamente baixo; a não utilização do preservativo entre as mulheres em relação estável foi atribuída à negativa do parceiro. Entre os entrevistados que declararam usar o preservativo, o tipo de relação estabelecida e a fase do relacionamento resultaram em padrões de uso diversificados; o uso consistente do preservativo foi mais frequente nas parcerias eventuais. CONCLUSÕES: O conhecimento incipiente aliado à prática sexual insegura coloca mulheres unidas, de baixa escolaridade, menor renda, sobretudo acima dos 45 anos, e os residentes de Recife em situação de maior vulnerabilidade às DST/aids.OBJECTIVE: The objective of this paper is to assess the level of knowledge and information held by the population about HIV/AIDS, and to analyze discourses about condom use and sexual practices. METHODS: Qualitative research with 64 young people and adults, black and white, sexually active men and women. Vulnerability to HIV/AIDS was discussed from the perspective of racial (black or white), generational (between 16 and 45 or 24 years or older) and gender (male or female). In-depth interviews were conducted with a semi-structured script in the cities of São Paulo (SP) and Recife (PE) on the following themes: knowledge and perception about STD/AIDS, perception of individual risk, negotiation and condom use, sexual initiation and practices. RESULTS: The least-educated, men, elders and residents of Recife were the least informed persons as regards to HIV/AIDS. People over 45 years and the less educated had incipient knowledge about transmission and prevention of STD/AIDS. Condom use among respondents in both cities was relatively low, non-use of condoms among women in stable relationship was attributed to partner's refusal to using it. Among respondents who reported using condoms, the type of relationship established and the phase of the relationship resulted in varied patterns of use; the consistent use of condoms was more common in occasional partnerships. CONCLUSIONS: The incipient knowledge in association with unsafe sexual practice puts women in stable relationship, poorly educated, lower income, particularly above 45 years, and residents of Recife in a situation of greater vulnerability to STD/AIDS