In vivo imaging reveals sigmoidal growth kinetic of ß-amyloid plaques.

ABSTRACT

A major neuropathological hallmark of Alzheimer's disease is the deposition of amyloid plaques in the brains of affected individuals. Amyloid plaques mainly consist of fibrillar ß-amyloid, which is a cleavage product of the amyloid precursor protein. The amyloid-cascade-hypothesis postulates Aß accumulation as the central event in initiating a toxic cascade leading to Alzheimer's disease pathology and, ultimately, loss of cognitive function. We studied the kinetics of ß-amyloid deposition in Tg2576 mice, which overexpress human amyloid precursor protein with the Swedish mutation. Utilizing long-term two-photon imaging we were able to observe the entire kinetics of plaque growth in vivo. Essentially, we observed that plaque growth follows a sigmoid-shaped curve comprising a cubic growth phase, followed by saturation. In contrast, plaque density kinetics exhibited an asymptotic progression. Taking into account the fact that a critical concentration of Aß is required to seed new plaques, we can propose the following kinetic model of ß-amyloid deposition in vivo. In the early cubic phase, plaque growth is not limited by Aß concentration and plaque density increases very fast. During the transition phase, plaque density stabilizes whereas plaque volume increases strongly reflecting a robust growth of the plaques. In the late asymptotic phase, Aß peptide production becomes rate-limiting for plaque growth. In conclusion, the present study offers a direct link between in vitro and in vivo studies facilitating the translation of Aß-lowering strategies from laboratory models to patients.