Monitoring protein aggregation and toxicity in Alzheimer's disease mouse models using in vivo imaging

Abstract

Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer's disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer's disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions.

Figure 1

Schematic of in vivo imaging.

Figure 2

Samples of data from in vivo imaging experiments in AD model mice. (a) shows an example of plaque formation (arrow points to new plaque, red) over 1 week with simultaneous imaging of YFP expressing neurites (green) and blood vessels (blue). We observe tangle formation (blue green, arrowhead points to new tangle labeled with thioflavin S in b) subsequent to caspase activation (red). We have also treated with anti Aβ antibodies (labeled with a red fluorophore, c), which decorate methoxy XO4 labeled dense cored plaques (blue/green). Dendritic spines loss has been observed in vivo (green, d) surrounding dense plaques (blue). Scale bars represent 50 μm (a), 20 μm (b, c), and 10 μm (d).