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Doenças neurodegenerativas: uma visão gliocêntrica
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Resumo(s)
As Doenças Neurodegenerativas compreendem um conjunto de entidades patológicas de apresentação clínica e fisiopatologia muito diversas, com uma prevalência crescente na sociedade moderna.
A acentuada perda neuronal nestas doenças parece refletir os efeitos cumulativos de múltiplos fenómenos patológicos, incluindo a neuroinflamação, agregação de proteínas, stress oxidativo e disfunção mitocondrial. Atualmente, reconhece-se que a neurodegeneração ocorre, em parte, na sequência da perturbação do ambiente neuronal e da perda consequente de homeostasia no Sistema Nervoso Central (SNC).
As células da glia, principalmente a microglia e os astrócitos, são reconhecidas como tendo uma contribuição vital para a excitabilidade neuronal, plasticidade sináptica e metabolismo energético, em muito ultrapassando o conceito de serem meros elementos do tecido conjuntivo entre neurónios. Estas desempenham um papel crítico no diálogo intercelular e na manutenção do equilíbrio entre a neuroproteção e a neurodegeneração. Neste sentido, a microgliose e a astrogliose reativas apresentam-se como características patológicas major, contribuindo para um estado exacerbado de inflamação que tende a persistir e a desencadear degeneração neural.
A presente monografia procura consolidar o conhecimento e a investigação científica relativos à biologia glial no contexto de algumas das mais comuns doenças neurodegenerativas, como a Doença de Alzheimer, Doença de Huntington, Doença de Parkinson e Esclerose Lateral Amiotrófica (ELA). É realizada uma abordagem centrada na diversidade e funções dos distintos tipos celulares da glia encontrados no SNC e nos principais fenómenos associadas a tais doenças, com foco nos papéis desempenhados pela microglia e pelos astrócitos, a par da complexa relação estabelecida entre ambos. Mais detalhadamente, identificam-se as consequências associadas à disfunção glial nas funções homeostáticas no âmbito das quatro doenças neurodegenerativas supracitadas, com enfâse particular na Doença do Neurónio Motor. Adicionalmente, indicam-se potenciais biomarcadores das células gliais, no contexto da ELA, bem como as perspetivas futuras relativas à investigação de estratégias terapêuticas.
Neurodegenerative diseases comprise a set of pathological entities with heterogeneous clinical presentation and pathophysiology, which are rapidly rising in prevalence, particularly in our society’s aging population. The insidious loss of neurons in these disorders seems to reflect the cumulative effects of numerous pathological features such as neuroinflammation, protein aggregation, oxidative stress, and mitochondrial dysfunction. There is now also accumulating evidence that suggests neurodegeneration takes place in part because the neuron’s environment is affected and brain homeostasis is lost, highlighting a non–cell-autonomous process. Nowadays glial cells, mainly astrocytes and microglia, are recognized for their crucial contribution to a plethora of physiological processes like neuronal excitability, synaptic plasticity, and energy metabolism, broadening the flawed concept that considered them merely as the connective tissue between neurons. Moreover, they display a central role in managing the intercellular crosstalk in both detrimental and beneficial ways. Accordingly, microgliosis and astrogliosis are now considered major pathological features, contributing to the heightened inflammatory state that persists and may lead to neurodegeneration. The present literature review consolidates the knowledge and research performed so far regarding the role of glia cells in several of the most encountered neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS). Firstly, it is addressed the diversity and function of glial cell types found in the central nervous system and major processes associated with neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their complex relationship. In specific, consequences of glial dysfunction on homeostatic functions in four of the major neurodegenerative diseases are identified, with special emphasis on ALS as a motor neuron disease. Additionally, potential biomarkers directed to glia in ALS are discussed, as well as the future and promising directions envisioned for the research of therapies targeting glial cells.
Neurodegenerative diseases comprise a set of pathological entities with heterogeneous clinical presentation and pathophysiology, which are rapidly rising in prevalence, particularly in our society’s aging population. The insidious loss of neurons in these disorders seems to reflect the cumulative effects of numerous pathological features such as neuroinflammation, protein aggregation, oxidative stress, and mitochondrial dysfunction. There is now also accumulating evidence that suggests neurodegeneration takes place in part because the neuron’s environment is affected and brain homeostasis is lost, highlighting a non–cell-autonomous process. Nowadays glial cells, mainly astrocytes and microglia, are recognized for their crucial contribution to a plethora of physiological processes like neuronal excitability, synaptic plasticity, and energy metabolism, broadening the flawed concept that considered them merely as the connective tissue between neurons. Moreover, they display a central role in managing the intercellular crosstalk in both detrimental and beneficial ways. Accordingly, microgliosis and astrogliosis are now considered major pathological features, contributing to the heightened inflammatory state that persists and may lead to neurodegeneration. The present literature review consolidates the knowledge and research performed so far regarding the role of glia cells in several of the most encountered neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS). Firstly, it is addressed the diversity and function of glial cell types found in the central nervous system and major processes associated with neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their complex relationship. In specific, consequences of glial dysfunction on homeostatic functions in four of the major neurodegenerative diseases are identified, with special emphasis on ALS as a motor neuron disease. Additionally, potential biomarkers directed to glia in ALS are discussed, as well as the future and promising directions envisioned for the research of therapies targeting glial cells.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Doenças neurodegenerativas Glia Microglia Astrócitos Neuroinflamação Mestrado integrado - 2021