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Selective inhibition of PCAF suppresses microglial-mediated β-amyloid neurotoxicity
Soo-Yeon Park1, Yoo-Hyun Lee, Ah-Reum Seong
1Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun‑gu, Seoul 120-752, Republic of Korea.
Abstract:
Recent studies have emphasized the functional role of the P300/CBP-associated factor (PCAF) enzyme in resistance to β-amyloid (Aβ)-mediated neurotoxicity; however, the underlying mechanisms through which PCAF regulates inflammation and neurotoxicity have not yet been elucidated. In this study, we used computer-based molecular docking simulations to perform structure-based artificial screening for PCAF-specific inhibitors. Our results revealed that one of the compounds from the screened library, compound C-11, selectively inhibited PCAF, but not p300 or GCN5, with a half-maximal inhibitory concentration (IC50) of approximately 0.25 µM. Furthermore, C-11 had no effects on the activities of other epigenetic enzymes. Western blot analysis using an antibody against acetyl-nuclear factor-κB (NF-κB) demonstrated that PCAF mediated the Aβ-induced activation of NF-κB by acetylation at Lys-122. We also found that the knockdown of PCAF completely inhibited Aβ-induced cytokine production in BV-2 cells in a similar manner to C-11 treatment. Finally, PCAF inhibition suppressed both Aβ-induced cytokine production and Aβ-mediated neuronal cell death. Therefore, our results suggest that in neuronal cells, PCAF is a promising therapeutic target for alleviating the inflammatory progression of Alzheimer's disease.
Insights
Researchers identified a PCAF inhibitor (C-11) that reduces beta-amyloid neurotoxicity. PCAF enzyme inhibition suppressed inflammation and neuronal cell death, suggesting PCAF as a therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The P300/CBP-associated factor (PCAF) enzyme is implicated in resistance to beta-amyloid (Aβ)-mediated neurotoxicity.
- The precise mechanisms by which PCAF influences neuroinflammation and neurotoxicity remain unclear.
Purpose of the Study:
- To investigate the role of PCAF in Aβ-induced neurotoxicity and inflammation.
- To identify and characterize PCAF-specific inhibitors for potential therapeutic intervention in Alzheimer's disease.
Main Methods:
- Computer-based molecular docking simulations were employed for structure-based screening of PCAF inhibitors.
- Compound C-11 was identified as a selective PCAF inhibitor.
- Western blot analysis was used to assess NF-κB acetylation and cytokine production.
- PCAF knockdown and C-11 treatment were used to evaluate their effects on Aβ-induced responses in BV-2 cells and neuronal cells.
Main Results:
- Compound C-11 selectively inhibited PCAF with an IC50 of approximately 0.25 µM, without affecting p300, GCN5, or other epigenetic enzymes.
- PCAF was found to mediate Aβ-induced activation of nuclear factor-κB (NF-κB) via acetylation at Lys-122.
- Knockdown of PCAF or treatment with C-11 significantly inhibited Aβ-induced cytokine production in BV-2 cells.
- PCAF inhibition effectively suppressed both Aβ-induced cytokine production and Aβ-mediated neuronal cell death.
Conclusions:
- PCAF plays a critical role in mediating Aβ-induced inflammation and neurotoxicity.
- Selective inhibition of PCAF presents a promising therapeutic strategy for mitigating the inflammatory progression of Alzheimer's disease.
