Researchers here outline an interesting approach to trapping misfolded amyloid-β before it can aggregate and disrupt the biochemistry of the brain. Without the ability to aggregate into solid structures, the misfolded amyloid-β will break down or be cleared without causing harm. It remains to be seen as to how well this does in practice, but it is certainly the case that safer, cheaper alternatives to the present anti-amyloid immunotherapies are much needed. It appears that amyloid-β is important only in the long lead in to Alzheimer's disease, and thus therapies are most effectively deployed very early and broadly, in a large fraction of the population. The cost and side-effect profile of present immunotherapies is not well suited to this sort of use case.
Most neurodegenerative conditions are characterized by the accumulation of misfolded proteins in the brain, leading to the progressive loss of neurons. To tackle this challenge, researchers turned to a class of peptide amphiphiles that contain modified chains of amino acids. Peptide amphiphiles are already used in well-known pharmaceuticals. "Trehalose is naturally occurring in plants, fungi, and insects. It protects them from changing temperatures, especially dehydration and freezing. Others have discovered trehalose can protect many biological macromolecules, including proteins. So, we wanted to see if we could use it to stabilize misfolded proteins."
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Surprisingly, the trehalose destabilized the nanofibers. Although it seems counterintuitive, this decreased stability exhibited a beneficial effect. Unstable assemblies of molecules are very reactive. Searching for stability, the nanofibers bonded to amyloid-beta proteins, a key culprit implicated in Alzheimer's disease. But the nanofibers didn't just stop the amyloid-beta proteins from clumping together. The nanofibers fully incorporated the proteins into their own fibrous structures - permanently trapping them into stable filaments.
"Then, it's no longer a peptide amphiphile fiber anymore, but a new hybrid structure comprising both the peptide amphiphile and the amyloid-beta protein. That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, are trapped. They can no longer penetrate the neurons and kill them. It's like a clean-up crew for misfolded proteins. This is a novel mechanism to tackle progression of neurodegenerative diseases, such as Alzheimer's, at an earlier stage. Current therapies rely on the production of antibodies for well-formed amyloid fibers."
View the full article at FightAging
