Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute ß-amyloid infusion model.
J Neuroinflammation
; 21(1): 196, 2024 Aug 06.
Article
in En
| MEDLINE
| ID: mdl-39107821
ABSTRACT
Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf ß-amyloid (Aß) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aß peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aß into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aß. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phagocytosis
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Mice, Transgenic
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Amyloid beta-Peptides
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Microglia
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Disease Models, Animal
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Focal Adhesion Kinase 2
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Alzheimer Disease
Limits:
Animals
/
Humans
Language:
En
Journal:
J Neuroinflammation
Journal subject:
NEUROLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Japan