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P4–316: Visualization of beta‐amyloid plaque reduction by small‐molecule beta‐amyloid oligomer aggregation inhibitors in hAPPSL transgenic mice
Author(s) -
Muhs Andreas,
Kroth Heiko,
Sreenivasachary Nampally,
Benderitter Pascal,
Hamel Anne,
Varisco Yvan,
Froestl Wolfgang,
Paganetti Paolo,
Pfeifer Andrea
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.08.268
Subject(s) - in vivo , genetically modified mouse , amyloid beta , medicine , amyloid (mycology) , beta (programming language) , transgene , pathology , pharmacology , disease , chemistry , biochemistry , biology , computer science , gene , programming language , microbiology and biotechnology
Background: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder affecting an estimated 35 million patients. Current treatment options are limited to drugs treating the symptoms and do not slow or reverse disease progression. Thus, a disease modifying drug would be a major therapeutic breakthrough towards treatment of the disease. The formation of A b fibrils and their deposition into neurotoxic amyloid plaques is considered an initial event in the progression of AD. A central therapeutic aim in AD is the removal of toxic amyloid-b deposit, which can be achieved by inhibition of Ab aggregation. Previously, we have identified a compound capable of reducing Ab plaques and improvingmemory capacity in tg-mice. Herein, we report the effect of this compound on longitudinal Ab plaque dynamics in tg-mice.Methods: Female hAPP SL tg-mice (9-12 months) were operated for implantation of a cranial window and tg-mice still having a transparent cranial window 4 weeks after implantation were used for the study. The combination of an intravenously administered imaging agent and in vivo two-photon microscopy allowed the visualization of densecore A b plaques on Day 0. The values obtained on Day 0 served as baseline in the subsequent 15 day long longitudinal study performed on the same animal treated orally once a day with either vehicle or compound. Results: The vehicle-treated tg-mice exhibited no clear trend to either growth or decrease in plaque size as the diameter of plaques on Day 15 did not differ statistically significant from Day 0, but the plaque density increased by 17 %. In contrast, compound treated tg-mice showed a strong, statistically significant decrease in the size of all pre-existing plaques as the plaque volume decreased by 75 % leading to a decrease in Ab plaque load. Conclusions: We have discovered a small molecule with suitable pharmacokinetic properties which prevented/reversed the pathological toxic effect of Ab aggregation leading to a statistically significant decrease in plaque size in an animal model of AD. Thus, this compound could be a promising candidate for the treatment of AD.