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Published on: January 28, 2019
Up-regulation of astrocyte metabotropic glutamate receptor 5 by amyloid-β peptide
Christopher S Casley1, Viktor Lakics, Hyoung-gon Lee
1Eli Lilly & Company Limited, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK.
Abstract:
The effects of amyloid-beta peptide (Aβ) on astrocyte responses to activation of mGlu5 receptors have been investigated using calcium imaging. Pre-incubation with Aβ1-40 peptide for up to 72 h produced a time- and concentration-dependent 2-4 fold enhancement in the magnitude of the intracellular calcium mobilization response to the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). In contrast, pre-treatment with Aβ1-40 did not alter the calcium responses induced by other G protein coupled- or ion channel-receptors. Aβ 1-40-enhanced DHPG responses were blocked by the mGlu5 antagonist MPEP but not by inhibitors of voltage dependent calcium channels or by the AMPA/KA receptor antagonist CNQX. Up-regulation of mGlu5 coupled responses was associated with significant increases in astrocyte mGlu5 receptor-mRNA and-protein expression after preincubation with Aβ . The changes observed in vitro were consistent with results obtained from human Alzheimer's disease (AD) patients.Immunostaining for mGlu5 receptors was increased on astrocytes which were colocalized with Aβ plaques in hippocampal tissue from AD patients compared to age-matched controls. These results suggest that modulation of mGlu5 receptors in astrocytes could be an important mechanism in determining the progression of pathology in AD.
Insights
Amyloid-beta peptides enhance astrocyte responses to mGlu5 receptor activation, potentially driving Alzheimer's disease pathology. This involves increased mGlu5 receptor expression in astrocytes near plaques.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Astrocytes play crucial roles in brain function and disease.
- Metabotropic glutamate receptor 5 (mGlu5) signaling is implicated in neurological disorders.
- Amyloid-beta (Aβ) peptides are central to Alzheimer's disease (AD) pathogenesis.
Purpose of the Study:
- To investigate the impact of amyloid-beta (Aβ) peptides on astrocyte responses mediated by metabotropic glutamate receptor 5 (mGlu5).
- To explore the potential role of Aβ-induced mGlu5 modulation in Alzheimer's disease progression.
Main Methods:
- Calcium imaging was used to measure astrocyte responses.
- Primary astrocyte cultures were pre-incubated with Aβ1-40 peptide.
- Responses to mGlu5 receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) were assessed.
- Immunohistochemistry was performed on human Alzheimer's disease brain tissue.
Main Results:
- Aβ1-40 pre-incubation time- and concentration-dependently enhanced astrocyte calcium responses to DHPG by 2-4 fold.
- This enhancement was specific to mGlu5 receptor activation, as responses to other receptors were unaffected.
- Aβ1-40 treatment led to increased astrocyte mGlu5 receptor mRNA and protein expression.
- Elevated mGlu5 receptor immunostaining was observed on astrocytes co-localized with Aβ plaques in human AD brain tissue.
Conclusions:
- Amyloid-beta peptides significantly enhance astrocyte responses via mGlu5 receptor activation.
- Increased mGlu5 receptor expression in astrocytes is associated with Aβ pathology.
- Modulation of astrocyte mGlu5 receptors represents a potential mechanism in Alzheimer's disease progression.
