Therapeutics could hitch a ride on cellular machinery.
German scientists have hijacked one of the cell’s own mechanisms to deliver a potential Alzheimer’s drug directly to where it is needed.
In so doing they have turned an obscure area of cell-biology research into one that could have wide applications in drug delivery.
The work is a very long way from the clinic. But experts see in it a useful approach to developing drug treatments for neurodegenerative diseases.
Cell membranes are made up different proteins embedded in a ‘sea’ of lipids. For the past twenty years, Kai Simons, a research director at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, has argued that this sea is not passive. He says that under some circumstances, ‘rafts’ — comprising a particular mixture of fats and protein molecules — emerge temporarily from within the sea to take part in some important biological function, and then disperse again.
One such function is endocytosis, in which the cell membrane forms a bubble to engulf one of its own proteins or an external molecule such as a virus. Newly assembled rafts let the membrane bend, says Simons, allowing a bubble to form. Once sealed, the bubble, known as an endosome, moves inside the cell, becomes acidified and breaks down its cargo.
Simons’s raft concept is somewhat controversial because it has been hard to prove. But in the past few years, powerful new technologies that allow individual molecules to be tracked in membranes have provided a lot of support. Now, Simons has shown how the idea might be used in therapy.
Simons knew that a protein called amyloid-ß peptide, which causes the plaques that lead to neurodegeneration in Alzheimer’s disease, is generated in endosomes by the enzyme ß-secretase. Previous studies have shown that, oddly, inhibitors of this enzyme don’t stop amyloid-ß plaques from forming in animal models of Alzheimer’s. Simons wondered if that was because the inhibitors don’t reach high enough concentrations where they need to be — in the endosomes.
With his co-workers, he engineered a form of enzyme inhibitor that would anchor itself to the membrane rafts, and so become concentrated in the endosomes. They did this by adding a sterol group, which attaches to the lipid mix present in rafts.
The anchored inhibitor worked well in cell culture, and worked in animal models too: it prevented plaque formation in the brains of fruitflies and mice that had been genetically engineered to mimic Alzheimer’s disease, Simons and his team report in Science1.
Proof of principle
“This particular test inhibitor isn’t druggable,” says Simons - it won't become an anti-Alzheimer's drug. “But it is proof of the general principle that you can use this approach to target drugs [to particular places] inside the cell.”
Simons admits that this is also not final proof that rafts exist in cell membranes, but it’s “yet another good piece of evidence”, he says.
Pharmacologist Michael Spedding, deputy director of research at the pharmaceutical company Servier in Paris, believes that rafts in brain cells will become important in drug development in neurodegenerative disease. “It’s an exciting bit of work,” he says.
But he warns that there may be an intrinsic problem to be resolved — raft-directed drugs have to be fat soluble by definition, but that means they will dissolve in all of the body’s fats, so it might be hard to target them to the right cells.
Rajendran, L. et al. Science 320, 520-523 (2008).