Objectives: Microglial overactivation, which is secondary to abnormalities of amyloid-beta peptide (Aβ) and tau proteins in the pathogenic cascade leading to onset of Alzheimers disease (AD), accelerates tau pathology, according to our recent observations using mouse models of tauopathies, and this positive feedback results in formation of a vicious cycle between upstream and downstream processes, potentially hampering effective suppression of the entire cascade by anti-amyloid treatments. This motivates our present work aimed at dual monitoring of amyloidosis and microgliosis in living animal models of AD, toward therapeutic regulation of these two processes capable of halting the self-perpetuating cycle. Methods: Transgenic mice expressing mutant amyloid precursor protein (APP23 mice) was examined by highresolution positron emission tomography (PET) after administration of amyloid probe, Pittsburg Compound B (PIB) synthesized with high specific radioactivity (SA). Microglial activation in these mice was also imaged by PET and specific tracer, [18F]fluoroethyl-DAA1106. Results: Progressive amyloidosis in APP23 mice was visualized by PET and high-SA PIB. In vitro assays revealed preferential binding of PIB to N-terminally modified Aβ, AβN3pE. As levels of this Aβ subspecies in model mice are lower than those in AD patients, our findings plausibly explain advantages of high-SA tracers in sensitive detection of mouse amyloid. Near-simultaneous monitoring of amyloid removal and microgliosis in APP23 mice following injection of anti-Aβ antibody demonstrated positive correlation between levels of initially existing amyloid and antibody-induced microglial activation, suggesting the possibility of microglial overactivation in immunotherapy for subjects with abundant amyloid. Conclusions: The present animal imaging system would substantially facilitate establishment of a safe and effective therapeutic strategy targeting multiple key processes in the AD pathogenesis.
Keywords: Amyloid, Aβ, tau, transgenic mouse, positron emission tomography, microglia, imaging biomarker