Author(s): Brown DA, Sarkar G, Decklever TD, Curran GL, Sarkar AJ, Schmeichel AM, Swaminathan SK, Kandimala KK, Jenkins RB, Burns TC and Lowe VJ
Objective: Transgenic mouse models are central to the study of Alzheimer’s disease and aid in elucidating the underlying pathophysiology. Mouse models also provide a system in which to test potential therapeutic strategies. PET imaging plays a central clinical role in diagnosing human cases of Alzheimer’s disease but has had variable performance in mouse models. We investigated the potential role of the K16ApoE carrier peptide to enhance delivery of a radiolabeled PET imaging tracer, 11C-PiB and assess whether this corresponds to improved sensitivity of the PET modality in APP/PS1 transgenic mice.
Methods: Brain-delivery of 11C-PiB was accomplished by sequential bolus injections of K16ApoE and 11C-PiB via femoral vein injections. Distribution of 11C-PiB to the brain and heart was quantified via dynamic PET/CT imaging and digital autoradiography.
Results: K16ApoE carrier peptide increased the brain uptake of 11C-PiB in both wild-type and APP/PS1 mice. Administration of K16ApoE increased the PET standard uptake value of 11C-PiB at 5 minutes in WT mice from 1.132 to 2.963 (p=0.006) and in APP/PS1 mice from 0.842 to 3.268 (p=0.016). Enhancement peaked at 5 minutes. Binding was reversible as demonstrable by Logan plots with similarly increased kinetics in both WT and APP/PS1 mice. The absolute values were higher in APP/PS1 mice suggesting increased retention. The increased retention in APP/PS1 mice was consistent with specific binding to Aβ plaques as unlabeled PiB showed competitive reduction of 11C-PiB signal retention.
Conclusion: K16ApoE-mediates enhancement of 11C-PiB signal in APP/PS1 mice brains with increase in the PET sensitivity. There is increased uptake kinetics in both WT and APP/PS1 mice with specific retention due to Aβ plaque binding in the latter. This improved sensitivity of PET scanning in the APP/PS1 transgenic mouse model. Such enhanced delivery of this PET tracer has implications for development and testing of new hypotheses and the efficacy of novel therapeutic paradigms.
