Development of an Antibody-Targeted PET Probe for Early Diagnostic Imaging of Alzheimer's Disease
Session Number
Q02
Advisor(s)
Erika Cline, Northwestern University William Klein, Northwestern University Kirsten Viola, Northwestern University
Location
A-123
Start Date
28-4-2016 1:35 PM
End Date
28-4-2016 2:00 PM
Abstract
There currently exist no methods to diagnose Alzheimer’s Disease (AD), which is the most common neurodegenerative disease characterized by progressive mental deterioration. The molecular focus on AD is shifting away from amyloid plaques and towards their peptide form- the amyloid-β oligomer (AβO). The pathology of AβOs and downstream tau more closely correlate with neuronal loss in comparison to amyloid plaques and have only been found in demented individuals, suggesting that AβOs initiate AD pathogenesis. We selected NU4 as our high-affinity, therapeutic antibody to direct our probe towards the desired target. In this study, we concluded that NU4 labels pathology distinct from traditional plaque stains and that NU4-DOTA retains its immunoreactivity to AβOs in vitro. Mice injected with NU4PET displayed a robust AD-dependent signal. The PET signal correlated with fluorescent intensity detected using immunofluorescent analysis. Human brains labeled with NU4 demonstrated pathology similar to that seen in mice, suggesting that mouse-derived NU4 can be used to target AβOs in humans. A study comparing age and sex dependence on AβO levels demonstrated that AβOs are present at 2 months of age in 5xFAD mice, 2-3 months before the onset of dementia. Conclusively, NU4PET demonstrates tremendous potential as an early diagnostic agent for AD.
Development of an Antibody-Targeted PET Probe for Early Diagnostic Imaging of Alzheimer's Disease
A-123
There currently exist no methods to diagnose Alzheimer’s Disease (AD), which is the most common neurodegenerative disease characterized by progressive mental deterioration. The molecular focus on AD is shifting away from amyloid plaques and towards their peptide form- the amyloid-β oligomer (AβO). The pathology of AβOs and downstream tau more closely correlate with neuronal loss in comparison to amyloid plaques and have only been found in demented individuals, suggesting that AβOs initiate AD pathogenesis. We selected NU4 as our high-affinity, therapeutic antibody to direct our probe towards the desired target. In this study, we concluded that NU4 labels pathology distinct from traditional plaque stains and that NU4-DOTA retains its immunoreactivity to AβOs in vitro. Mice injected with NU4PET displayed a robust AD-dependent signal. The PET signal correlated with fluorescent intensity detected using immunofluorescent analysis. Human brains labeled with NU4 demonstrated pathology similar to that seen in mice, suggesting that mouse-derived NU4 can be used to target AβOs in humans. A study comparing age and sex dependence on AβO levels demonstrated that AβOs are present at 2 months of age in 5xFAD mice, 2-3 months before the onset of dementia. Conclusively, NU4PET demonstrates tremendous potential as an early diagnostic agent for AD.