Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells. A hallmark pathological feature of Alzheimer’s disease (AD) is the accumulation of extracellular plaques composed of the amyloid-beta (Aβ) peptide.
Researchers at the University of California, Santa Cruz, (UCSC) report they have discovered a segment of the amyloid-beta protein that is recognized by receptors involved in neuronal uptake of this toxic peptide.
Their findings, “Evidence for aggregation-independent, PrPC-mediated Aβ cellular internalization,” published in Proceedings of the National Academy of Sciences, suggest that targeting this process may be a promising approach for Alzheimer’s drug development.
“There are many different ways that amyloid beta can be toxic inside cells, so wouldn’t it be nice if we could block its uptake by neurons? This is a pathway we can target,” said Jevgenij Raskatov, assistant professor of chemistry and biochemistry at UCSC.
“Evidence linking amyloid beta (Aβ) cellular uptake and toxicity has burgeoned, and mechanisms underlying this association are subjects of active research. Two major, interconnected questions are whether Aβ uptake is aggregation-dependent and whether it is sequence-specific,” noted the researchers.
The researchers, led by graduate student Alejandro Foley and postdoctoral researcher Graham Roseman, PhD, sought to test whether the prion protein also acts as a receptor to take up soluble forms of amyloid beta, and to identify the site within amyloid beta that binds to this receptor.
Researchers used a strategy based on previous work from Raskatov’s lab using mirror-image versions of amyloid beta to show that cellular uptake is mostly mediated by receptors on the cell surface.
After testing the peptides in the library for cellular uptake, the researchers found that amino acids Aβ (1–30) do not aggregate but display cellular uptake stereospecificity when compared to its mirror image. This finding suggests that Aβ uptake is predominantly receptor-mediated and may be independent from its aggregation state. They also discovered the segment is soluble and does not form aggregates because it is missing a long hydrophobic domain involved in the aggregation of amyloid beta into clumps and fibrils.
“With this shortened amyloid beta, we are able to decouple cellular uptake from aggregation, giving us a great model for studying uptake,” Raskatov added.
For the first time, researchers demonstrated the prion protein’s role in cellular uptake of soluble amyloid beta, consistent with its selectivity for the L stereoisomer of amyloid beta.
Their findings show that the binding of amyloid beta at the cell surface, leading to its internalization, is largely due to the amino acid sequence 1–30 and not the state of aggregation. When amyloid beta molecules begin to aggregate, they form “oligomers” consisting of a small number of molecules stuck together that are still soluble and can be taken up by neurons. These soluble oligomers are increasingly considered to be the form of amyloid beta that triggers the pathological processes leading to Alzheimer’s disease, but there are many different aggregated forms.
“The initial steps leading to Alzheimer’s disease may be the prion protein-mediated transport of soluble amyloid beta into neurons, where it then clumps, forming toxic aggregates that ultimately lead to the characteristic plaques associated with the disease,” noted Millhauser.
“Our findings open up new avenues for understanding Alzheimer’s and suggest promising strategies for therapeutics,” Millhauser said.
Their results highlight the potential of targeting cellular surface receptors to inhibit Aβ cellular uptake as an alternative route for future therapeutic development for Alzheimer’s disease.