APP causes an energy crisis

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...