Dresden: Proof of principle for new approach to treating Alzheimer’s

Research lead

JADO Technologies GmbH says it reached proof of principle for a new approach to preventing the formation of beta amyloid, one of the main constituents of the plaques that develop in the brains of Alzheimer’s disease sufferers.

The approach is based on the company’s Raft platform technology in which small molecule inhibitors are targeted at the microdomains, or rafts, in the cell membrane. These are rafts are small compartments, which in effect provide a discrete reaction vessel for the many molecular process that take place in the cell membrane.

The research is the fruit of work with academic collaborators at three Dresden institutes – the Max Planck Institute of Molecular Cell Biology, the Technical University of Dresden, and Biotec– and the Göttingen-based Max Planck Institute for Experimental Medicine and the Center of Neurological Medicine. The scientists have shown that beta-secretase, the rate-limiting enzyme in the production of the beta-amyloid peptide, can be inhibited effectively using compounds anchored to cell membrane Rafts.

Unlike existing approaches to beta-secretase inhibition that do not take account of the intracellular location of the target protein, or the different conformation that the protein may assume in this context, these Raft inhibitors are delivered to the exact site where beta-secretase executes its neurotoxic activity.

“Our data provide proof-of principle of a new approach for directing small molecule inhibitors to disease-causing Raft targets in cellular membranes,” said Kai Simons, of the Max Planck Institute of Molecular Cell Biology and Genetics and co-founder of Dresden-based JADO. “By directing inhibition to the sub-compartment where the enzyme is active, this approach could be used in the design of more effective beta-secretase inhibitors for the treatment of Alzheimer’s disease.”

The strategy could also be used to design therapeutics against other Raft targets in a range of other diseases.

Beta-secretase is internalised from the cell membrane into intracellular compartments (endosomes) where it cleaves its substrate, amyloid precursor protein (APP). Most soluble inhibitors of beta-secretase cannot reach intracellular targets. The researchers first tested whether anchoring of a beta-secretase inhibitor to the membrane would confer inhibitory activity upon it by bringing it to the right compartment.

A peptide inhibitor of beta-secretase, which inhibited soluble beta-secretase but failed to block the enzyme in a cellular assay, was coupled to a sterol anchor molecule and a potent inhibition of beta-secretase activity demonstrated.

Concentrations as low as 100 nM of the anchored inhibitor were sufficient to completely block appearance of amyloid peptide. In an animal model of Alzheimer’s disease, the same anchored inhibitor reduced beta-amyloid formation in the brain by 50 per cent over 4 hours, whereas the free inhibitor was ineffective.

The advantage of using a sterol anchor is that it targets and increase the concentration of the inhibitor in the sterol-rich Raft domains where beta-secretase cleaves APP. The company also has data showing that the Raft anchor could not be substituted by any other lipid type, demonstrating its knowledge of Raft chemistry is crucial.