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Molecular imaging of Alzheimer’s disease–related gamma-secretase in mice and nonhuman primates
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2020
- Publisher :
- Rockefeller University Press, 2020.
-
Abstract
- Alzheimer’s disease–related γ-secretase is a prime drug target whose brain regional expression and distribution remain largely unknown. This study describes the development of a molecular imaging probe to reveal γ-secretase in rodents and macaques with translational potentials in humans.<br />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.
- Subjects :
- Male
0301 basic medicine
Transgene
Immunology
Mice, Transgenic
Biology
Pathogenesis
03 medical and health sciences
0302 clinical medicine
Neuroimaging
Alzheimer Disease
Positron Emission Tomography Computed Tomography
Presenilin-1
medicine
Animals
Humans
Immunology and Allergy
Gamma secretase
medicine.diagnostic_test
Drug discovery
Brief Definitive Report
Brain
Magnetic resonance imaging
Macaca mulatta
Magnetic Resonance Imaging
Imaging agent
Molecular Imaging
030104 developmental biology
Amyloid Precursor Protein Secretases
Molecular imaging
Neuroscience
Human Disease Genetics
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 217
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....cea5f2fd5479c28bb6c5bc785e14feee