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Published on: August 11, 2023
Microglial cells kill prion-damaged neurons in vitro by a CD14-dependent process
Clive Bate1, Ronald Boshuizen, Alun Williams
1Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK. cbate@rvc.ac.uk
Abstract:
Microglial cells killed primary cortical neurons exposed to the prion (PrP)-derived peptide HuPrP106-126. The survival of HuPrP106-126-damaged neurons was increased by pre-treating microglial cells with anti-CD14 antibodies, while microglial cells from CD14 knockout mice failed to kill HuPrP106-126-damaged neurons. In addition, HuPrP106-126-damaged neurons selectively bound a CD14-IgG chimera. The killing of HuPrP106-126-damaged neurons by human monocytes was epitope specific; it was reduced by pre-treating monocytes with some anti-CD14 monoclonal antibodies (mabs) (60bca, 3C10 or MAB3832), but not others (26ic or MAB3831). None of the mabs affected the survival of HuPrP106-126-damaged neurons in the absence of monocytes.
Insights
Microglial cells contribute to neuronal death from prion peptides. Blocking CD14 on microglia or monocytes protected neurons, indicating CD14
Area of Science:
- Neuroscience
- Immunology
- Prion Diseases
Background:
- Prion diseases are associated with neuronal damage and death.
- Microglia are the primary immune cells in the central nervous system and play a role in neuroinflammation.
- The prion-derived peptide HuPrP106-126 is implicated in neuronal toxicity.
Purpose of the Study:
- To investigate the role of microglial cells in the killing of primary cortical neurons exposed to the prion-derived peptide HuPrP106-126.
- To determine the involvement of CD14 in the microglial-mediated neurotoxicity.
- To explore the potential therapeutic implications of targeting CD14.
Main Methods:
- Primary cortical neurons were exposed to the prion-derived peptide HuPrP106-126.
- Microglial cells were pre-treated with anti-CD14 antibodies or obtained from CD14 knockout mice.
- Human monocytes were used to assess CD14 epitope specificity in neurotoxicity.
- CD14-IgG chimeras were used to study binding interactions.
Main Results:
- Microglial cells were found to kill primary cortical neurons exposed to HuPrP106-126.
- Pre-treatment of microglia with anti-CD14 antibodies or the use of CD14 knockout microglia significantly increased neuronal survival.
- HuPrP106-126-damaged neurons selectively bound a CD14-IgG chimera.
- Monocyte-mediated killing of HuPrP106-126-damaged neurons was epitope-specific, with certain anti-CD14 monoclonal antibodies reducing toxicity.
Conclusions:
- CD14 plays a critical role in microglial-mediated neurotoxicity induced by the prion-derived peptide HuPrP106-126.
- Targeting CD14 on microglia and monocytes may represent a therapeutic strategy for prion-related neurodegenerative diseases.
- The findings highlight a specific mechanism of immune-mediated neuronal damage in prion diseases.
