| First Author | Matsuzaki M | Year | 2023 |
| Journal | Mol Psychiatry | Volume | 28 |
| Issue | 4 | Pages | 1802-1812 |
| PubMed ID | 36721026 | Mgi Jnum | J:351747 |
| Mgi Id | MGI:7663179 | Doi | 10.1038/s41380-023-01946-y |
| Citation | Matsuzaki M, et al. (2023) ADAMTS4 is involved in the production of the Alzheimer disease amyloid biomarker APP669-711. Mol Psychiatry 28(4):1802-1812 |
| abstractText | Amyloid-beta (Abeta) deposition in the brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD). We have previously identified amyloid precursor protein (APP)669-711 (a.k.a. Abeta(-3)-40) in human plasma using immunoprecipitation combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (IP-MALDI-MS). Furthermore, we found that the level of a composite biomarker, i.e., a combination of APP669-711/Abeta1-42 ratio and Abeta1-40/Abeta1-42 ratio in human plasma, correlates with the amyloid PET status of AD patients. However, the production mechanism of APP669-711 has remained unclear. Using in vitro and in vivo assays, we identified A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) as a responsible enzyme for APP669-711 production. ADAMTS4 cleaves APP directly to generate the C-terminal stub c102, which is subsequently proteolyzed by gamma-secretase to release APP669-711. Genetic knockout of ADAMTS4 reduced the production of endogenous APP669-711 by 30% to 40% in cultured cells as well as mouse plasma, irrespectively of Abeta levels. Finally, we found that the endogenous murine APP669-711/Abeta1-42 ratio was increased in aged AD model mice, which shows Abeta deposition as observed in human patients. These data suggest that ADAMTS4 is involved in the production of APP669-711, and a plasma biomarker determined by IP-MALDI-MS can be used to estimate the level of Abeta deposition in the brain of mouse models. |
