Using the mulitphoton micrsocopy imaging technique, senile plaques of Alzheimer's disease can be detected in the brains of living transgenic mice, and characterized with chronic imaging.
This detection platform was used to characterize a therapeutic approach to clearing the senile plaques based on immunotherapy, as well as to characterize novel amyloid-targeting ligands in preclinical development for PET imaging in humans.
Current research is aimed at optimizing anti-amyloid- therapeutic approaches, and imaging the anatomy and physiology of specific cell types in the brain before and after treatment. Development of novel optical techniques is ongoing, and includes methods to measure protein-protein interactions using fluorescence lifetime imaging microscopy (FLIM), and non-invasive approaches to amyloid imaging in intact animals.
Brian J. Bacskai, PhD
Serial in-vivo imaging of ceregral amyloid agiopathy (CAA) in a Tg2576 mouse starting at 10.3 months. The images shown are at the 4th, 5th and 6th week of imaging. CAA deposition proceeds mostly through propagation of existing deposits. Robbins et al.
Amyloid plaques alter the morphology and trajectory of neurites in-vivo. GFP filled neurites (in green) curve around the plaque (blue, stained with methoxy-XO4, rather than penetrating the plaque. The arrow indicates a distrophic neurite. Blood vessels contain Texas Red Dextran. Spires et al.
A FLIM pseudocolor representation of a senile plaque labeled with fluorescent 3d6 and 10d5 exhibiting flourescent energy transfer (FRET). Lifetimes are not uniform throughout the plaque, but rather show a reduction at the periphery (red) as compared to the core (blue/green). Bacskai et al.
F(ab)2 fragments of 3d6 are equally effective as full length 3d6 at clearing away diffuse amyloid.(green) after three days in the PDAPP mouse model. Bacskai et al.
Dense core plaques activate the fluorogenic activator Amplex Red in-vivo (A). Histochemical marker ThioFlavin-S confirms the presence of the dense core plaque (C). McLellan et. al.
Imaging of an intact mouse brain from a 22 month Tg2576 mouse imaged after staining with ThioFlavin-S. By 22 months, Tg2576 mice develop extensive CAA. Domnitz et. al.
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