Resting microglia react to Aß42 fibrils but do not detect oligomers or oligomer-induced neuronal damage.
Neurobiol Aging
; 35(11): 2444-2457, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-24973120
ABSTRACT
In Alzheimer's disease (AD), amyloid-ß (Aß) deposits accumulate in the brain parenchyma and contain fibrils of aggregated heterogeneous Aß peptides. In addition to fibrils, Aß aggregates into stable soluble species (termed Aß oligomers), which are increasingly viewed as the key drivers of early neurodegenerative events in AD. Aß aggregates stimulate microglia recruitment and activation. In the AD brain, microglia surround Aß deposits, activate, and abnormally produce inflammatory mediators, contributing to AD pathogenesis. However, it remains unclear to which of the conformationally diverse Aß species microglia specifically react. Here, we explore the "sensor" capability of murine microglia. We examine whether they can detect and discriminate the toxic Aß oligomers, Aß fibrils, and Aß-induced neuronal damage and investigate whether they are activated by diverse human Aß species cell autonomously or through neuron-derived factors. We find that, on aggregation in vitro, Aß42 peptides form stable oligomers and fibrils, which are neurotoxic and trigger dendritic spine loss in mature primary mouse hippocampal neurons. Further, in resting primary murine microglia, Aß42 fibrils induce a pattern of expression of inflammatory genes typical of the classical inflammatory response induced by infectious agents (e.g., the bacterial toxin lipopolysaccharide). Conversely, Aß42 oligomers never elicit a microglia inflammatory response, whether applied alone, in combination with neuron-derived secreted factors, or in contact with neurons. Thus, microglia strongly react to Aß42 fibrils, but do not sense Aß oligomers or oligomer-induced neuronal damage. This suggests that early neurotoxic species can escape detection by microglia, leading to the chronic unfolding of amyloid pathology in AD.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Microglia
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Doença de Alzheimer
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Agregação Patológica de Proteínas
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Agregados Proteicos
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Amiloide
Limite:
Animals
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Pregnancy
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article