Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I

We analyzed the mechanism of axonal transport of the amyloid precursor prot ein (APP), which plays a major role in the development of Alzheimer's disea se. Coimmunoprecipitation, sucrose gradient, and direct in vitro binding de monstrated that APP forms a complex with the microtubule motor, conventiona l kinesin (kinesin-1), by binding directly to the TPR domain of the kinesin light chain (KLC) subunit. The estimated apparent K-d for binding is 15-20 nM, with a binding stoichiometry of two APP per KLC. In addition, associat ion of APP with microtubules and axonal transport of APP is greatly decreas ed in a gene-targeted mouse mutant of the neuronally enriched KLC1 gene. We propose that one of the normal functions of APP may be as a membrane cargo receptor for kinesin-1 and that KLC is important for kinesin-1-driven tran sport of APP into axons.