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Updated: May 24, 2026
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
Published on: January 31, 2019
Nucleotides released from Aβ₁₋₄₂ -treated microglial cells increase cell migration and Aβ₁₋₄₂ uptake through P2Y₂
Hye Jung Kim1, Deepa Ajit, Troy S Peterson
1Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
Abstract:
Amyloid β-protein (Aβ) deposits in brains of Alzheimer's disease patients generate proinflammatory cytokines and chemokines that recruit microglial cells to phagocytose Aβ. Nucleotides released from apoptotic cells activate P2Y(2) receptors (P2Y(2) Rs) in macrophages to promote clearance of dead cells. In this study, we investigated the role of P2Y(2) Rs in the phagocytosis and clearance of Aβ. Treatment of mouse primary microglial cells with fibrillar (fAβ(1-42) ) and oligomeric (oAβ(1-42) ) Aβ(1-42) aggregation solutions caused a rapid release of ATP (maximum after 10 min). Furthermore, fAβ(1-42) and oAβ(1-42) treatment for 24 h caused an increase in P2Y(2) R gene expression. Treatment with fAβ(1-42) and oAβ(1-42) aggregation solutions increased the motility of neighboring microglial cells, a response inhibited by pre-treatment with apyrase, an enzyme that hydrolyzes nucleotides. The P2Y(2) R agonists ATP and UTP caused significant uptake of Aβ(1-42) by microglial cells within 30 min, which reached a maximum within 1 h, but did not increase Aβ(1-42) uptake by primary microglial cells isolated from P2Y(2) R(-/-) mice. Inhibitors of α(v) integrins, Src and Rac decreased UTP-induced Aβ(1-42) uptake, suggesting that these previously identified components of the P2Y(2) R signaling pathway play a role in Aβ phagocytosis by microglial cells. Finally, we found that UTP treatment enhances Aβ(1-42) degradation by microglial cells, but not in cells isolated from P2Y(2) R(-/-) mice. Taken together, our findings suggest that P2Y(2) Rs can activate microglial cells to enhance Aβ clearance and highlight the P2Y(2) R as a therapeutic target in Alzheimer's disease.
Insights
P2Y(2) receptors (P2Y(2) Rs) on microglial cells enhance amyloid-beta (Aβ) clearance in Alzheimer's disease models. Activating these receptors boosts Aβ uptake and degradation, suggesting P2Y(2) Rs as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques that trigger neuroinflammation.
- Microglial cells are key immune cells in the brain responsible for clearing Aβ.
- Nucleotide receptors, such as P2Y(2) receptors (P2Y(2) Rs), are involved in immune cell functions.
Purpose of the Study:
- To investigate the role of P2Y(2) Rs in microglial phagocytosis and clearance of Aβ.
- To determine if P2Y(2) R activation influences Aβ uptake and degradation by microglial cells.
Main Methods:
- Primary mouse microglial cells were treated with fibrillar (fAβ) and oligomeric (oAβ) forms of Aβ(1-42).
- ATP and UTP, P2Y(2) R agonists, were used to assess Aβ uptake and degradation.
- Experiments were conducted using wild-type and P2Y(2) R knockout (P2Y(2) R(-/-)) microglial cells.
Main Results:
- Aβ treatment induced ATP release and increased P2Y(2) R gene expression in microglial cells.
- P2Y(2) R agonists (ATP, UTP) significantly enhanced Aβ(1-42) uptake by wild-type microglial cells.
- UTP treatment promoted Aβ(1-42) degradation in a P2Y(2) R-dependent manner.
- Signaling pathways involving α(v) integrins, Src, and Rac were implicated in UTP-induced Aβ uptake.
Conclusions:
- P2Y(2) Rs play a crucial role in mediating microglial phagocytosis and clearance of Aβ.
- Activation of P2Y(2) Rs enhances both the uptake and degradation of Aβ by microglial cells.
- P2Y(2) Rs represent a potential therapeutic target for improving Aβ clearance in Alzheimer's disease.
