Bibliographic
Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer’s disease. We have now attached a retro-inverted version of the HIV protein transduction domain ‘TAT’ to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH2) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1DE9 transgenic mice. Daily intraperitoneal injection of RIOR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1DE9 mice resulted in a 25% reduction (p,0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p,0.0001) of b-amyloid plaque count, a 44% reduction (p,0.0001) in the numbers of activated microglial cells, and a 25% reduction (p,0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p,0.0001), all compared to control APPswe/PS1DE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer’s disease.
Therapeutic Agent
Animal Model
Experimental Design
Male mice were used for experiments with Flu-RI-OR2-TAT. Female mice were used for experiments with RI-OR2-TAT.