Alzheimer drugs incorporated in nanoparticles for specific transport over the blood brain barrier

Drugs against AD have been successfully tested in vitro but failed in patients due to minimal blood brain barrier (BBB) penetrance. To overcome that issue the consortium of the current project will develop nanoparticles crossing the BBB more effectively. Furthermore, we will establish in vitro BBB models to determine the kinetics of receptor mediated nanoparticle transport. Basically the models will consist of an endothelial monolayer having properties similar to the BBB. Within JSW Life Sciences` parts of the project, the medium collected after transport over the endothelial monolayer most probably containing significant amounts of intact nanoparticles will be applied to primary cultured chicken neurons which express APP and secrete Aß40 and Aß42. The chicken neurons are prepared from eight days old chicken embryos. The chicken model is of specific importance to this project since it was found to be very effective to evaluate GSMs for their efficacy to change amyloid secretion. Primary neurons are more likely to precisely mimic the human -secretase complex than transgenic cell lines or other systems. This represents an important aspect since the investigation of GSMs is more critical in that regard than e.g. clear competitive -secretase inhibition. In vivo testing experiments of the nanoparticle formulations represent the other contribution of JSW Life Sciences to the ERA-NET-project. The experiments will be performed in transgenic mice overexpressing human amyloid precursor protein carrying the Swedish and London mutations. The latter are suitable to study amyloid pathology as well as inflammation. To investigate behavioral alterations the Morris Water Maze Test (MWM) will be performed. Biochemical evaluations will comprise the quantification of Beta Amyloid 1-40 and 1-42 in CSF as well as in brain tissue. Primary histological evaluations will focus on amyloid pathology using well established protocols for detection of plaques in hAPP tg mice at JSW Life Sciences. In addition to behavioral, biochemical and histological evaluations the animals will undergo MRI examinations in cooperation with the Medical University Graz.

One of the difficult obstacles to treat brain diseases is to deliver pharmacologically active compounds to the brain at a dose that ensures an effective treatment of the disease. The challenge is to permeate the blood brain barrier. The main task of the latter is to protect the brain from outside factors comparable to a firewall that is built around the core part of the nervous system.Nanoparticles were found capable to overcome that barrier. During this project nanoparticles comprising human serum albumin, Apolipoprotein E and magnetite were successfully produced. The main reason to implement Apolipoprotein E was to improve the nanoparticles capability to selectively enter the brain. Magnetite was added to allow the tracking of the particles by magnetic resonance imaging in live rats. The latter were used as a model organism. Finally it was possible to detect the nanoparticles in the brain of live animals using a magnetic resonance imaging scanner. Furthermore, the findings were corroborated by the histologic evaluation after the termination of the animals. So it was shown that both methods were able to trace nanoparticle accumulation in the brain, with histology post mortem and above all with classical magnetic resonance scanners. Finally it was possible to produce nanoparticles carrying Flurbiprofen, an anti-inflammatory compound that might be effective to treat Alzheimers disease. Project partners in Germany and Israel performed nanoparticle synthesis and in vitro work while the Austrian team did the in vivo part, histology and MRI work.