Interfering in the Interaction between Amyloid-β and Prion Protein as a Treatment for Alzheimer's Disease

The damage of Alzheimer's disease mediated by aggregation of amyloid-β and tau protein deposits isn't so much due to the aggregates, but rather the surrounding halo of complex interactions and related proteins. One of those thought to be important is between oligomeric amyloid-β and cellular prion protein, the latter of which is also of note in transmissible spongiform encephalopathy. Researchers here sought to interfere in this interaction, and achieved interesting results, at least in a mouse model of Alzheimer's disease. The usual caveats apply, in that Alzheimer's mouse models are highly artificial constructs, since nothing resembling Alzheimer's naturally occurs in that species. The relevance of these varied models to the real condition is very dependent on the details of the model and the details of the treatment - there is plenty of room for later failure even given good results in mice.

Researchers have identified a drinkable cocktail of designer molecules that interferes with a crucial first step of Alzheimer's and even restores memories in mice. The binding of amyloid beta peptides to prion proteins triggers a cascade of devasting events in the progression of Alzheimer's - accumulation of plaques, a destructive immune system response, and damage to synapses.

Researchers screened tens of thousands of compounds looking for molecules that might interfere with the damaging prion protein interaction with amyloid beta. They found that an old antibiotic looked like a promising candidate but was only active after decomposing to form a polymer. Related small polymers retained the benefit and also managed to pass through the blood-brain barrier. They then dissolved the optimized polymeric compound and fed it to mice engineered to have a condition that mimics Alzheimer's. They found that synapses in the brains were repaired and mice recovered lost memory.

A collaborating team reported a positive response when they delivered the same cocktail to cells modeled to have Creutzfeldt-Jakob Disease, a devasting neurological condition caused by infection with misfolded prion protein. The next step is to verify the compounds aren't toxic in preparation for translation to clinical trials for Alzheimer's disease.


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