APP (green) gets stuck in mitochondria (red).

Although the normal occupation of the transmembrane amyloid precursor protein (APP) is not fully understood, its rogue activity is well documented. An APP cleavage product known as Aβ accumulates in plaques and tangles that are the hallmark of Alzheimer's disease (AD). Anandatheerthavarada et al. now report that APP is also targeted to and can damage mitochondria (page 41).

The researchers realized that APP carries a dual zip code that can send a protein to either the endoplasmic reticulum or the mitochondria. Although the amount of APP that normally gets sent to mitochondria is small, they found a significant amount of it there in studies of both cultured cells and transgenic AD mice.

An acidic domain in APP causes the protein to get stuck in the mitochondrial transport channels. This impairs mitochondrial energy output, probably because it blocks the import of normal freight. These problems correlate with the mitochondrial dysfunction and sharp decrease in energy output seen in AD patients, implicating a new pathway of APP-mediated neuronal injury in AD.

Factors that increase the targeting of APP to mitochondria are under investigation. At present, APP is not known to have a normal function in mitochondria. But if targeting of APP to the cell powerhouse is something of an accident, it is certainly a very costly one. ▪