New Therapeutic Approach from Stem Cell-Aided Study of Alzheimer’s Proteins
The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments.
The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition.
Improving the trafficking of these cellular proteins in brain cells holds possibilities for new treatments and even prevention for Alzheimer’s disease, results of a new study suggest. Researchers found that a compound that enhances the shuttling of proteins within cells reduced the production of forerunners of two proteins implicated in brain cell death.
Recent research suggests that these proteins accumulate because of a defect in the system that ferries proteins within the cell. The proteins are
shipped in membrane-bound packages, called endosomes. The system that shuttles them around the cell is the endosomal network. For proteins to be properly processed, eliminated or recycled, this system must function correctly.The retromer is a key player in directing how the endosomal “packages” are shuttled about in the endosomal network to be delivered to the right destination.
The researchers found that the compound, called R33, did enhance the function of the retromer. They then administered this compound to their lab-grown stem cells and then measured production of amyloid beta and tau. R33 had been shown in animal studies to boost the function of the retromer. And, in fact, it did lead to a “considerable reduction” in the production of both amyloid-beta and tau, according to a press release.
“The findings suggest that something upstream is affecting the production of amyloid beta and phosphorylated-Tau independently,” said lead author is Jessica Young, assistant professor of pathology at the UW School of Medicine in Seattle. “So one thing we’re going to work on going forward will be using these cell lines to identify what this upstream defect might be and whether it, too, could be a target for new therapeutics to treat Alzheimer’s.“
