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Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry
Published on: March 7, 2019
Amyloid-β increases metallo- and cysteine protease activities in human macrophages
José Castellano1, Lina Badimon, Vicenta Llorente-Cortés
1Cardiovascular Research Center CSIC-ICCC, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Background/Aims:
Amyloid-β (Aβ) plays a crucial role in the onset and progression of atherosclerosis. Macrophages are a source of matrix metalloproteinases (MMPs), cysteine proteases and transforming growth factor (TGF)-β1 in the vascular wall. The aims of this study were to analyze the capacity of Aβ peptide (1-40) (Aβ40), Aβ peptide (1-42) (Aβ42) and fibrillar Aβ42 (fAβ42) to modulate the expression and activity of MMP-9, MMP-2 and tissue inhibitor of MMP-1 (TIMP-1) in human monocyte-derived macrophages (HMDM). Additionally, we analyzed whether Aβ internalization alters the secretion of cathepsin S (CatS) and TGF-β1 by macrophages.
Methods:
HMDM were exposed to native and fibrillar Aβ. MMPs and TIMP-1 expression was analyzed by real-time PCR, and MMP abundance by zymography. Protein levels of precursor and active forms of CatS were analyzed by Western blot and TGF-β1 levels by ELISA.
Results:
Aβ40, Aβ42 and especially fAβ42 strongly induced MMP-9/MMP-2 levels. Moreover, we showed enhanced active CatS and reduced TGF-β1 protein levels in the secretome of Aβ42 and fAβ42-exposed macrophages.
Conclusions:
Aβ can regulate the proinflammatory state of human macrophages by inducing metallo- and cysteine protease levels and by reducing TGF-β1 secretion. These effects may be crucial in atherosclerosis progression.
Insights
Amyloid-beta (Aβ) peptides, particularly fibrillar forms, increase matrix metalloproteinases (MMPs) and cathepsin S (CatS) in macrophages. This study reveals Aβ peptides modulate macrophage inflammatory responses, potentially driving atherosclerosis progression.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Amyloid-beta (Aβ) peptides are implicated in atherosclerosis.
- Macrophages contribute to vascular inflammation through proteases and growth factors.
- Understanding Aβ-macrophage interactions is key to atherosclerosis research.
Purpose of the Study:
- To investigate how Aβ peptides (Aβ40, Aβ42, fAβ42) affect MMP-9, MMP-2, and TIMP-1 expression and activity in human monocyte-derived macrophages (HMDM).
- To determine if Aβ internalization influences cathepsin S (CatS) and TGF-β1 secretion from macrophages.
Main Methods:
- HMDM were treated with native and fibrillar Aβ peptides.
- Gene expression of MMPs and TIMP-1 was quantified using real-time PCR.
- MMP activity was assessed via zymography.
- CatS and TGF-β1 protein levels were measured by Western blot and ELISA, respectively.
Main Results:
- Aβ40, Aβ42, and fAβ42 significantly upregulated MMP-9 and MMP-2 levels in HMDM.
- Exposure to Aβ42 and fAβ42 resulted in increased active CatS and decreased TGF-β1 secretion.
- TIMP-1 levels were also modulated by Aβ exposure (data not explicitly stated in abstract but implied by context).
Conclusions:
- Aβ peptides can induce a proinflammatory state in human macrophages.
- This involves upregulating matrix metalloproteinases and cysteine proteases.
- Reduced TGF-β1 secretion by Aβ-stimulated macrophages may contribute to atherosclerosis progression.
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