While the normal function of the amyloid precursor protein (APP) remains unknown, senior author Narayan G. Avadhani and his colleagues have determined that a mere 50-amino-acid stretch of the protein wreaks havoc by essentially starving mitochondria and the cells they nourish.
"We found that when APP leaves the nucleus, it can be directed both to mitochondria and to the endoplasmic reticulum," said Avadhani, professor of biochemistry and chair of the Department of Animal Biology in Penn's School of Veterinary Medicine. "APP has an acidic, negatively charged region that causes it to jam irreversibly while traversing protein transport channels in the mitochondrial membrane. This hampers, and eventually completely blocks, mitochondria's ability to import other proteins and produce cellular energy."
As if suffocating the cell's power plant weren't enough, jammed APP proteins also damaged the mouse neurons studied by Avadhani and co-author Hindupur K. Anandatheerthavarada in a second way. The end of the protein left dangling outside the mitochondrion contains a toxic product called A-Beta. The Penn researchers found that this toxin, a known component of the brain plaques and tangles that are a hallmark of Alzheimer's, is cleaved from the rest of the immobilized protein and accumulates in the cell.
"Researchers have observed many biochemical and biophysical phenomena associated with Alzheimer's disease," said Anan
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Contact: Steve Bradt
bradt@pobox.upenn.edu
215-573-6604
University of Pennsylvania
14-Apr-2003