Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates
© 2020 Xu et al..
The pathogenesis of Alzheimer's disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing γ-secretase. We used our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expression, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:217 |
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| Enthalten in: |
The Journal of experimental medicine - 217(2020), 12 vom: 07. Dez. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Yulong [VerfasserIn] |
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| Links: |
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| Themen: |
Amyloid Precursor Protein Secretases |
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| Anmerkungen: |
Date Completed 11.03.2021 Date Revised 21.07.2021 published: Print Citation Status MEDLINE |
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| doi: |
10.1084/jem.20182266 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315087161 |
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| 100 | 1 | |a Xu, Yulong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Xu et al. | ||
| 520 | |a The pathogenesis of Alzheimer's disease (AD) is primarily driven by brain accumulation of the amyloid-β-42 (Aβ42) peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. γ-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing γ-secretase. We used our recently developed γ-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [11C]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging γ-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high γ-secretase expression, suggesting a functional conservation of γ-secretase. Collectively, we have provided the first molecular brain imaging of γ-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Amyloid Precursor Protein Secretases |2 NLM | |
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| 700 | 1 | |a Wang, Changning |e verfasserin |4 aut | |
| 700 | 1 | |a Wey, Hsiao-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Yingxia |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zude |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Se Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Ran, Chongzhao |e verfasserin |4 aut | |
| 700 | 1 | |a Rynearson, Kevin D |e verfasserin |4 aut | |
| 700 | 1 | |a Bernales, Daniela R |e verfasserin |4 aut | |
| 700 | 1 | |a Koegel, Robert E |e verfasserin |4 aut | |
| 700 | 1 | |a Fiedler, Stephanie A |e verfasserin |4 aut | |
| 700 | 1 | |a Striar, Robin |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Steven L |e verfasserin |4 aut | |
| 700 | 1 | |a Tanzi, Rudolph E |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Can |e verfasserin |4 aut | |
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