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Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration
Pedro Garção1, Catarina R Oliveira, Paula Agostinho
1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Abstract:
The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.
Insights
Amyloid-beta (Abeta) and prion protein (PrP) peptides activate microglia, leading to neuronal death. Interleukin-6 (IL-6) released by these activated microglia is a key factor in causing neuronal injury in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia activation is central to inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE).
- Amyloid-beta (Abeta) peptides in AD and pathogenic prion protein (PrPSc) in PRE are implicated in neuronal death and gliosis.
- The specific mechanisms by which Abeta and PrP peptides activate microglia and induce neuronal damage are not fully elucidated.
Purpose of the Study:
- To investigate if Abeta and PrP peptides directly activate microglia.
- To determine if these peptides differentially affect microglia.
- To assess if substances released by activated microglia induce neuronal death.
Main Methods:
- Primary rat microglia cultures were treated with synthetic Abeta1-40, Abeta1-42, and PrP106-126 peptides.
- Lipopolysaccharide (LPS) served as a positive control for microglia activation.
- Nitric oxide, hydroperoxides, inducible nitric oxide synthase (iNOS), and cytokine (IL-1beta, IL-6) production were measured.
- Microglia-neuron co-cultures were used to assess neuronal death, with and without IL-6 neutralization.
Main Results:
- Abeta1-40 and PrP106-126 induced similar morphological changes, increased nitric oxide and hydroperoxide production, and upregulated iNOS expression in microglia.
- These peptides differentially affected the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6).
- Microglia activated by Abeta1-40 or PrP106-126 induced comparable neuronal death in co-cultures, which was significantly reduced by IL-6 neutralization.
Conclusions:
- Abeta and PrP peptides are direct activators of microglia.
- These peptides differentially modulate microglia cytokine secretion profiles.
- Interleukin-6 released by reactive microglia plays a critical role in mediating Abeta- and PrP-induced neuronal injury.
