RRC ID 82151
Author Lee JW, Mizuno K, Watanabe H, Lee IH, Tsumita T, Hida K, Yawaka Y, Kitagawa Y, Hasebe A, Iimura T, Kong SW.
Title Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute β-amyloid infusion model.
Journal J Neuroinflammation
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 β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ 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 Aβ 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 Aβ. 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.
Volume 21(1)
Pages 196
Published 2024-8-6
DOI 10.1186/s12974-024-03192-7
PII 10.1186/s12974-024-03192-7
PMID 39107821
PMC PMC11301859
MeSH Alzheimer Disease* / metabolism Alzheimer Disease* / pathology Amyloid beta-Peptides* / metabolism Animals Disease Models, Animal* Focal Adhesion Kinase 2* / antagonists & inhibitors Focal Adhesion Kinase 2* / metabolism Humans Mice Mice, Inbred C57BL Mice, Transgenic* Microglia* / drug effects Microglia* / metabolism Phagocytosis* / drug effects Phagocytosis* / physiology
Resource
Human and Animal Cells MG6(RCB2403)