Dataset Information

Amyloid-β_1-42 oligomers enhance mGlu₅R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

ABSTRACT: Synaptic weakening and loss are well-correlated with the pathology of Alzheimer's disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluRs) that is disrupted in rodent models of AD. Exogenous application of oAβ (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu₅R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both N-methyl-D-aspartate receptors (NMDARs) and complement C5aR1 signaling. Our findings reveal a mechanistic interaction between mGlu₅R, NMDARs, and the complement system in aberrant synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.

SUBMITTER: Ng AN

PROVIDER: S-EPMC10694656 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Amyloid-β<sub>1-42</sub> oligomers enhance mGlu<sub>5</sub>R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

Ng Ai Na AN Salter Eric W EW Georgiou John J Bortolotto Zuner A ZA Collingridge Graham L GL

iScience 20231107 12

Synaptic weakening and loss are well-correlated with the pathology of Alzheimer's disease (AD). Oligomeric amyloid beta (oAβ) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oAβ. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutama ...[more]

PMID: 38053635

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Project description:BackgroundAlzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

Dataset Information

Amyloid-β_1-42 oligomers enhance mGlu₅R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

Publications

Amyloid-β<sub>1-42</sub> oligomers enhance mGlu<sub>5</sub>R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

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Dataset Information

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

Publications

Amyloid-β<sub>1-42</sub> oligomers enhance mGlu<sub>5</sub>R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Amyloid-β_1-42 oligomers enhance mGlu₅R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling.