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Published on: January 30, 2014
Residual Microglia Following Short-term PLX5622 Treatment in 5xFAD Mice Exhibit Diminished NLRP3 Inflammasome and
Abstract:
Chronic neuroinflammation represents a prominent hallmark of Alzheimer's disease (AD). While moderately activated microglia are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations have indicated that the elimination of ∼80% of microglia through a month-long inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration without impacting Aβ levels. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the immediate effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglial phenotype or metabolic fitness are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ∼65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia demonstrated a noninflammatory phenotype, with highly branched and ramified processes and reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced in number with diminished Clec7a (dectin-1) expression. Additionally, both microglia and neurons displayed reduced mechanistic target of rapamycin (mTOR) signaling and autophagy. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling, and enhanced autophagy. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.
Insights
Short-term inhibition of colony-stimulating factor 1 receptor (CSF1R) in early Alzheimer's disease models preserves beneficial microglia. This approach reduces neuroinflammation and enhances autophagy without affecting amyloid plaques.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chronic neuroinflammation is a key feature of Alzheimer's disease (AD).
- Microglia, immune cells in the brain, can be beneficial or detrimental depending on their activation state.
- Previous studies showed long-term CSF1R inhibition reduces neuroinflammation and neurodegeneration in advanced AD models.
Purpose of the Study:
- To investigate the effects of short-term CSF1R inhibition during early neuroinflammation in 5xFamilial AD (5xFAD) mice.
- To determine the impact on residual microglial phenotype and metabolic state.
- To assess changes in neuroinflammation markers, signaling pathways, and autophagy.
Main Methods:
- 10-day inhibition of CSF1R in 3-month-old female 5xFAD mice.
- Analysis of microglial depletion, phenotype, inflammasome complexes (NLRP3), and dectin-1 expression.
- Assessment of mTOR signaling, autophagy, amyloid-beta (Aβ) levels, and neurogenesis.
Main Results:
- ~65% microglia depletion in hippocampus and cerebral cortex.
- Remaining microglia showed a non-inflammatory phenotype with reduced NLRP3 inflammasome.
- Decreased mTOR signaling and increased autophagy in both microglia and neurons.
- No significant changes in Aβ plaques, soluble Aβ-42, or neurogenesis.
Conclusions:
- Short-term CSF1R inhibition in early AD stages promotes homeostatic microglia.
- This treatment diminishes inflammasome activation and mTOR signaling while enhancing autophagy.
- The findings suggest a potential therapeutic window for CSF1R inhibition in early AD.
