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Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.

ABSTRACT: 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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC7553790 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.

Xu Yulong Y Wang Changning C Wey Hsiao-Ying HY Liang Yingxia Y Chen Zude Z Choi Se Hoon SH Ran Chongzhao C Rynearson Kevin D KD Bernales Daniela R DR Koegel Robert E RE Fiedler Stephanie A SA Striar Robin R Wagner Steven L SL Tanzi Rudolph E RE Zhang Can C

The Journal of experimental medicine 20201201 12

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 ou ...[more]

PMID: 32936886

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Project description:BackgroundSelectins are adhesion molecules that are expressed by the vascular endothelium upon activation and may be an imaging target for detecting myocardial ischemia long after resolution. The aim of this study was to test the hypothesis that molecular imaging of selectins with myocardial contrast echocardiographic (MCE) molecular imaging could be used to detect recent brief ischemia in closed-chest nonhuman primates.MethodsMyocardial ischemia was produced in anesthetized adult rhesus macaques (n = 6) by percutaneous balloon catheter occlusion of the left anterior descending or circumflex coronary artery for 5 to 10 min. Three separate macaques served as nonischemic controls. MCE perfusion imaging was performed during coronary occlusion to measure risk area and at 100 to 110 min to exclude infarction. MCE molecular imaging was performed at 30 and 90 min after reperfusion using a lipid microbubble bearing dimeric recombinant human P-selectin glycoprotein ligand-1 (MB-YSPSL). Collection of blood for safety data, electrocardiography, and echocardiography were performed at baseline and before and 10 min after each MB-YSPSL injection.ResultsVital signs, oxygen saturation, electrocardiographic results, ventricular systolic function, pulmonary vascular resistance, and serum safety markers were unchanged by intravenous injection of MB-YSPSL. On echocardiography, left ventricular dysfunction in the risk area had resolved by 30 min, and there was no evidence of infarction on MCE perfusion imaging. On selectin-targeted MCE molecular imaging, signal enhancement was greater (P < .05) in the risk area than remote territory at 30 min (25 ± 11 vs 11 ± 4 IU) and 90 min (13 ± 3 vs 3 ± 2 IU) after ischemia. There was no enhancement (<1 IU) in control nonischemic subjects.ConclusionsIn primates, MCE molecular imaging of selectins using MB-YSPSL, a recombinant ligand appropriate for humans, is both safe and effective for imaging recent myocardial ischemia. This technique may be useful for detecting recent ischemia in patients with chest pain even in the absence of necrosis.

Dataset Information

Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.

Publications

Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.

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