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The slow but steady decline into the fog of Alzheimer's disease currently affects about four million Americans. The disease, in which toxic plaques form and interfere with brain function, remains untreatable. But a report published online today by the Journal of Cell Biology provides further insight into how the disease wreaks havoc in the brain. The findings point to a new way in which a protein long associated with the condition can kill neurons--by sealing off their energy-producing mitochondria.
The jumbled plaques associated with Alzheimer's are the work of toxic amyloid proteins. Hindupur K. Anandatheerthavarada and his colleagues at the University of Pennsylvania studied a known source of these harmful peptides, amyloid precursor protein (APP), in mouse neurons. They found that the molecule can travel into a cell's mitochondria, but its structure causes problems during this journey. "APP has an acidic, negatively charged region that causes it to jam irreversibly while traversing protein transport channels in the mitochondrial membrane," explains study co-author Narayan G. Avadhani. "This hampers, and eventually completely blocks, mitochondria's ability to import other proteins and produce cellular energy." As a result, the cell suffers an energy crisis and dies. What is more, the team determined that the part of the protein that remains outside of a cell's mitrochondria still produces the deleterious beta amyloid that can accumulate within the cell, forming the telltale plaques.
The scientists determined that a section of the protein just 50 amino acids long is responsible for the starvation. When the researchers engineered a mutant version of APP that lacked this region, it successfully passed into the mitochondria without causing problems. Says Avadhani: "This suggests that pharmaceuticals could be developed to fix this domain, either by neutralizing its charge or folding it more tightly."
