Cientistas revertem a formação de placas de Alzheimer em modelos animais, aumentando a atividade do canal iônico chave
A perda da atividade de um canal iônico chave no cérebro pode contribuir para o acúmulo de uma proteína devastadora e tóxica responsável pelos aglomerados de placas que se acumulam na doença de Alzheimer, descobriu uma equipe de neurobiólogos na Chin
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)
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A perda da atividade de um canal iônico chave no cérebro pode contribuir para o acúmulo de uma proteína devastadora e tóxica responsável pelos aglomerados de placas que se acumulam na doença de Alzheimer, descobriu uma equipe de neurobiólogos na China.
Surpreendentemente, esta equipa também demonstrou – pelo menos em estudos com modelos animais – que esta proteína, uma característica fundamental da doença de Alzheimer, pode ser diminuída no cérebro vivo através da manipulação do canal iónico.
A proteína suspeita é a beta-amilóide , que se torna difundida no tecido cerebral de pacientes com doença de Alzheimer. A amiloide - tóxica e pegajosa se acumula em maços entre os neurônios e interrompe a função dessas células cerebrais vitais. O canal iônico é conhecido simplesmente como TRPM7 e pode contribuir para o acúmulo de -amiloide tóxico quando o próprio canal deixa de funcionar adequadamente, de acordo com cientistas do Laboratório Estatal de Neurobiologia Médica da Universidade Fudan, em Xangai.
“A agregação tóxica de - amilóide em neurônios está implicada na patologia da doença de Alzheimer”, afirmou o principal autor Shimeng Zhang, reportando na revista Science Signaling . . Zhang faz parte de uma grande equipe que conduz pesquisas contínuas sobre a atividade do canal iônico TRPM7 no laboratório em Xangai.
O canal TRPM7 estudado por Zhang e colegas é um poro especial na membrana dos neurônios, que permite a passagem de íons carregados do ambiente celular externo para o santuário interno da célula. O canal TRPM7 está envolvido na captação de cátions divalentes, como Zn 2+ , Mg 2+ e Ca 2+ . O canal iônico, portanto, ajuda a moldar atividades celulares críticas, como excitabilidade, plasticidade e metabolismo.
Mas TRPM7 é uma proteína de dupla função que é ao mesmo tempo um canal iônico e uma quinase . Por mais difícil que seja imaginar, este constituinte complexo na membrana neuronal é também uma enzima – uma quinase – que catalisa a transferência de grupos fosfato de alta energia de moléculas potentes de ATP para atividades de combustível que envolvem TRPM7. O mau funcionamento dos canais iônicos TRPM7 tem sido associado não apenas à doença de Alzheimer, mas a várias outras doenças neurodegenerativas, mostraram estudos.
Numa parte do estudo da equipa que examinou o tecido cerebral humano, Zhang e colegas descobriram que a quantidade de TRPM7 era substancialmente baixa em amostras cerebrais post-mortem de pacientes com doença de Alzheimer e em dois modelos diferentes de ratos com patologia induzida por - amilóide.
Zhang e colegas confirmaram em sua pesquisa que a perda da atividade do canal iônico TRPM7 pode contribuir para o acúmulo de proteínas amilóides tóxicas na doença de Alzheimer. Suas descobertas também podem fornecer uma ligação mecanicista entre a perda de TRPM7 e a patologia amilóide em pacientes que sofrem com a condição de roubo mental.
Os cientistas de Xangai não só revelaram na sua investigação que o TRPM7 diminui na doença de Alzheimer, como também conduziram uma série de experiências com modelos de ratos e mostraram que quantidades diminuídas de TRPM7 nas membranas celulares resultaram na acumulação de - amiloide.
Ciente de que o TRPM7 é uma proteína de funcionamento duplo (um canal iônico e uma quinase), a equipe fez uma pergunta aparentemente simples: e se aumentarmos a quantidade de comprimento total do canal iônico TRPM7 um grupo de animais e fornecer ao outro grupo uma abundância da porção quinase da molécula?
Num grupo de ratos idosos que foram criados para detectar a presença de - amilóide no tecido cerebral, os cientistas aumentaram a quantidade de TRPM7 de comprimento total nestes animais, superexpressando-o substancialmente. Nesse experimento, a equipe colaborativa descobriu que, ao aumentar a quantidade de moléculas TRPM7 de comprimento total, eles foram capazes de restaurar a formação de sinapses e a função cognitiva nos ratos. A porção quinase da molécula é conhecida como M7CK.
Então, em animais mais jovens, a porção de quinase sozinha foi introduzida e superexpressa. E quando o M7CK foi testado nesta coorte, a quinase ativou diretamente uma cascata de atividades. Por exemplo, a protease, MMP14, promoveu a degradação e depuração da - amilóide. A quinase realmente ajudou a varrer a destrutiva - amilóide dos cérebros desses animais. Na verdade, a equipe – pelo menos no laboratório – encontrou uma maneira de restaurar a atividade sináptica e a função cognitiva em um grupo de ratos e a eliminação da - amilóide tóxica no outro.
“Descobrimos que a atividade quinase do TRPM7 é importante para estimular a degradação da - amilóide”, relatou Zhang. "A expressão de TRPM7 foi diminuída em amostras de tecido do hipocampo de pacientes com doença de Alzheimer e dois modelos de camundongos com DA. Em culturas de neurônios do hipocampo de camundongos, a superexpressão do TRPM7 completo ou de seu domínio funcional de quinase M7CK evitou a perda de sinapses induzida por A exógeno. "
A superexpressão de M7CK manteve a função cognitiva em camundongos jovens pré-sintomáticos e restaurou a formação de sinapses e a função cognitiva em camundongos idosos. Estudos posteriores revelaram que o M7CK ativou diretamente a enzima MMP14, que promoveu a degradação e depuração da - amilóide.
Por mais promissora que a nova pesquisa pareça, os cientistas de todo o mundo ainda não disseram definitivamente se as placas amilóides são a causa da doença. Embora claramente tóxicas para o cérebro, as formações de placas podem ocorrer após uma série mais sutil de eventos deletérios que ainda não foram descobertos.
Além disso, outra proteína, conhecida simplesmente como tau, forma filamentos fibrosos insolúveis no cérebro que se acumulam como emaranhados neurofibrilares. Assim como alguns cientistas propuseram que as placas são uma possível causa da doença, outros argumentaram a favor da tau.
Em última análise, o seu sinergismo também pode contar uma história mais profunda sobre a génese da doença de Alzheimer. Juntas, as placas amilóides e os emaranhados neurofibrilares da tau criam as placas e emaranhados característicos da doença.
A doença de Alzheimer também tem sido associada a uma série de variantes genéticas diferentes, mas a maioria dos casos ocorre “esporadicamente”, o que significa que a doença não pode ser atribuída a uma causa específica. E sejam genéticas ou esporádicas, as placas amilóides pegajosas são uma característica definidora da doença para a qual não há cura. Só nos EUA, os custos totais de cuidados de saúde relacionados com a doença ascendem a 355 mil milhões de dólares anualmente, mostram dados da Associação de Alzheimer.
A menos que seja encontrada uma cura, espera-se que a doença sobrecarregue os sistemas globais de saúde até 2050, devido ao envelhecimento inexorável das populações, segundo a Organização Mundial de Saúde.
“Nossos resultados mostram que a patologia [da doença de Alzheimer] está associada a uma redução na expressão de TRPM7 e que manter a expressão normal de seu domínio quinase é suficiente para reduzir o acúmulo de - amilóide, proteger a densidade sináptica e prevenir ou reverter déficits de memória”, concluiu Zhang.
Mais informações: Shimeng Zhang et al, a atividade da TRPM7 quinase induz a degradação do ?-amilóide para reverter déficits sinápticos e cognitivos em modelos de camundongos da doença de Alzheimer, Science Signaling (2023). DOI: 10.1126/scisignal.ade6325
Informações da revista: Sinalização Científica