PHILADELPHIA -- Opening a new front in the battle against Alzheimer's disease, scientists at the University of Pennsylvania have found that a protein long associated with the disease inflicts grave damage in a previously unimagined way: It seals off mitochondria in affected neurons, resulting in an "energy crisis" and buildup of toxins that causes cells to die. This pathway, the first specific biochemical explanation for pathologies associated with Alzheimer's, is detailed in the April 14 issue of the Journal of Cell Biology.

While the normal function of the amyloid precursor protein (APP) re-mains 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 phe-nomena associated with Alzheimer's disease," said Anandatheerthavarada, research assistant professor of biochemistry and the paper's first author, "but it has remained unclear whether these are causes of Alzheimer's or merely side effects. The pathway we observed, which leads directly to common symptoms, is the first with a demonstrated ability to cause the neuronal death associated with Alzheimer's disease."

The results are consistent with the progressive nature of Alzheimer's and other neurodegenerative diseases, the scientists said. As pores in the mi-tochondrial membrane clog with proteins