High levels of APP-BP1 (white), as found in Alzheimer's patients (right), kills neurons.

The consequences of amyloid formation by the amyloid precursor protein (APP) in Alzheimer's disease (AD) have been the focus of many studies, yet little is known about the nonpathogenic function of APP. On page 27, some progress is made in this direction by Chen et al., who show that APP induces a suicide pathway in neurons.

APP initiates this death-inducing cascade when it encounters the binding protein APP-BP1. High levels of APP in neurons, or the APP mutant version associated with AD, promoted the recruitment of APP-BP1 to lipid rafts and activated its death-inducing activity. Past in vitro work has shown that APP-BP1 activates the ubiquitin-like protein NEDD8. NEDD8 conjugation of proteins such as Cullin (part of the SCF complex) drives entry into the cell cycle. In neurons, this push into mitosis somehow causes cell death rather than division. Chen et al. show that the APP-induced death also requires NEDD8 activation, as well as interaction of APP-BP1 with an intracellular domain of APP.

Unusually high levels of APP-BP1 and active NEDD8 were found in brain tissue from AD patients. Thus, constitutive activation of APP-BP1–mediated cell death may contribute to AD. The authors speculate that, under normal conditions, APP-BP1 remains inactive unless APP is bound by some as-yet unidentified extracellular ligand. The physiological relevance of this neuronal death program is unknown, but cloning of the APP ligand may offer some insight. ▪