| First Author | Kikuchi K | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 28 | Pages | 6173-6185 |
| PubMed ID | 34099509 | Mgi Jnum | J:348433 |
| Mgi Id | MGI:6723721 | Doi | 10.1523/JNEUROSCI.2595-20.2021 |
| Citation | Kikuchi K, et al. (2021) GPR120 signaling controls amyloid-beta degrading activity of matrix metalloproteinases. J Neurosci |
| abstractText | Alzheimer disease (AD) is characterized by the extensive deposition of amyloid-beta peptide (Abeta) in the brain. Brain Abeta level is regulated by a balance between Abeta production and clearance. The clearance rate of Abeta is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Abeta clearance mechanisms affects the pathological process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Abeta via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including omega3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Abeta-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Abeta-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120 specific antagonist substantially decreased the levels of Tris-buffered saline-soluble Abeta in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Abeta degrading activity of MMPs.SIGNIFICANT STATEMENTThe level of amyloid beta (Abeta) in the brain is a crucial determinant of the development of Alzheimer disease. Here we found that astrocytes, which are the most abundant cell type in the central nervous system, harbors degrading activity against amyloid beta, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Abeta-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Abeta therapeutics. |
