PlosOne dergisinde yayınlanan bir makaleye göre laboratuar ortamında geliştirilen inhibitör maddenin (RI-OR2-TAT) farelerde amiloid gelişimini azalttığı bulundu. Makalenin özetini ve ilgili haberi ilginize sunuyoruz. – TürkPsikiyatri | Geriatrik Psikiyatri (02/02/2013)
A Novel Retro-Inverso Peptide Inhibitor Reduces Amyloid Deposition, Oxidation and Inflammation and Stimulates Neurogenesis in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease
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/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-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/PS1ΔE9 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.
Vadivel Parthsarathy, Paula L. McClean, Christian Hölscher, Mark Taylor, Claire Tinker, Glynn Jones, Oleg Kolosov, Elisa Salvati, Maria Gregori, Massimo Masserini, David Allsop. A Novel Retro-Inverso Peptide Inhibitor Reduces Amyloid Deposition, Oxidation and Inflammation and Stimulates Neurogenesis in the APPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease. PLoS ONE, 2013; 8 (1): e54769 DOI: 10.1371/journal.pone.0054769
Professor David Allsop and Dr Mark Taylor at Lancaster University have successfully created a new drug which can reduce the number of senile plaques by a third, as well as more than doubling the number of new nerve cells in a particular region of the brain associated with memory. It also markedly reduced the amount of brain inflammation and oxidative damage associated with the disease.
The drug was tested on transgenic mice containing two mutant human genes linked to inherited forms of Alzheimer’s, so that they would develop some of the changes associated with the illness. The drug is designed to cross the blood-brain barrier and prevent the Aβ molecules from sticking together to form plaques.
Professor Allsop, who led the research and was the first scientist to isolate senile plaques from human brain, said: “When we got the test results back, we were highly encouraged. The amount of plaque in the brain had been reduced by a third and this could be improved if we gave a larger dose of the drug, because at this stage, we don’t know what the optimal dose is.”
The drug needs to be tested for safety before it can enter human trials, but, if it passes this hurdle, the aim would be to give the drug to people with mild symptoms of memory loss before they develop the illness.
“Many people who are mildly forgetful may go on to develop the disease because these senile plaques start forming years before any symptoms manifest themselves. The ultimate aim is to give the drug at that stage to stop any more damage to the brain, before it’s too late.”
The other researchers include groups led by Prof. Christian Hölscher at Ulster University, who conducted the mouse studies, and Prof. Massimo Masserini at University of Milano-Bicocca, Italy, who measured the ability of the drug to bind to Aβ.
Support for the research was given by Alzheimer’s Research UK, and the results are published in the open access journal PLOS ONE.
Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said: “We are pleased to have supported this study, which represents the first step to developing much-needed new treatments to fight Alzheimer’s. These are promising early-stage results, and several years more work will be required to assess the potential of this approach. For science like this to make a real difference to people’s lives, we must continue to invest in research.”