ADAMTS4 is involved in the production of the Alzheimer disease amyloid biomarker APP669-711

Amyloid-β (Aβ) 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. Aβ(-3)-40) in human plasma using immunoprecipitation combined with matrix-assisted laser desorption ionizatio...

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Bibliographic Details
Published in:Molecular psychiatry 2023-04, Vol.28 (4), p.1802-1812
Main Authors: Matsuzaki, Masaya, Yokoyama, Miyabishara, Yoshizawa, Yota, Kaneko, Naoki, Naito, Hiroki, Kobayashi, Honoka, Korenaga, Akihito, Sekiya, Sadanori, Ikemura, Kentaro, Opoku, Gabriel, Hirohata, Satoshi, Iwamoto, Shinichi, Tanaka, Koichi, Tomita, Taisuke
Format: Article
Language:English
Subjects:
ADAM protein
ADAMTS4 Protein
Aged
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - genetics
Amyloid precursor protein
Amyloid Precursor Protein Secretases - metabolism
Animal models
Animals
Biomarkers
Humans
Immunoprecipitation
Ions
Mass spectroscopy
Mice
Neurodegenerative diseases
Parenchyma
Plasma
Secretase
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods
Thrombospondin
β-Amyloid
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Summary:Amyloid-β (Aβ) 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. Aβ(-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/Aβ1-42 ratio and Aβ1-40/Aβ1-42 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 γ-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 Aβ levels. Finally, we found that the endogenous murine APP669-711/Aβ1-42 ratio was increased in aged AD model mice, which shows Aβ 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 Aβ deposition in the brain of mouse models.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-023-01946-y