Measurement of Tau Protein and Aβ Amyloid Plaques in Postmortem Human Brains of Down Syndrome and Alzheimer's Disease by Using [(125)I]IPPI and [(125)I]IBETA Autoradiography.

The accumulation of tau tangles and Aβ plaques are prominent neuropathologies that characterize Alzheimer's disease (AD) and Down syndrome (DS). Continuous developments of PET tracers as biomarkers can be supported by autoradiography to validate effectiveness and accuracy of binding properties that elucidate the pathophysiology of DSAD and AD. This in vitro comparative study evaluates [(125)I]IPPI binding to tau and [(125)I]IBETA binding to Aβ plaques in the frontal cortex (FCX) and temporal cortex (TCX) of postmortem human brain slices of AD (n = 5), DSAD (n = 5), and cognitively normal (CN) (n = 5) cases. With anti-tau and anti-Aβ immunostains confirming the presence of tau and Aβ plaques, [(125)I]IPPI and [(125)I]IBETA binding in autoradiographic images were significantly higher in DSAD and AD gray matter (GM) compared to CN. When comparing DSAD with AD, FCX and TCX GM binding was similar throughout DSAD and AD, except in FCX GM where there was 48% more [(125)I]IPPI binding in DSAD than AD. In vitro drug inhibition studies revealed that [(125)I]IPPI binding was significantly inhibited with increasing harmine concentrations (IC(50) = 115 nM) in DSAD FCX and TCX, but KuFal194, a DYRK1A drug, minimally inhibited [(125)I]IPPI binding in the same cases. The GM/white matter ratios for DSAD ([(125)I]IPPI = 4.1, [(125)I]IBETA = 2.9) and AD ([(125)I]IPPI = 4.2, [(125)I]IBETA = 2.6) were significantly greater than CN ([(125)I]IPPI = 1.3, [(125)I]IBETA = 1.2). A positive correlation between [(125)I]IPPI and [(125)I]IBETA binding suggests a synergistic relationship between tau and Aβ plaque in DSAD and AD pathology. This study demonstrates that [(125)I]IPPI and [(125)I]IBETA may serve as novel radiotracers in both DSAD and AD to continue diagnostic investigations.