Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP

Proteolytic processing of amyloid precursor protein (APP) generates amyloid -beta peptide and has been implicated in the pathogenesis of Alzheimer's di sease(1). However, the normal function of APP, whether this function is rel ated to the proteolytic processing of APP, and where this processing takes place in neurons in vivo remain unknown. We have previously shown that the axonal transport of APP in neurons is mediated by the direct binding of APP to the kinesin light chain subunit of kinesin-I, a microtubule motor prote in(2). Here we identify an axonal membrane compartment that contains APP, b eta -secretase and presenilin-1. The fast anterograde axonal transport of t his compartment is mediated by APP and kinesin-I. Proteolytic processing of APP can occur in the compartment in vitro and in vivo in axons. This prote olysis generates amyloid-beta and a carboxy-terminal fragment of APP, and l iberates kinesin-I from the membrane. These results suggest that APP functi ons as a kinesin-I membrane receptor, mediating the axonal transport of bet a -secretase and presenilin-1, and that processing of APP to amyloid-beta b y secretases can occur in an axonal membrane compartment transported by kin esin-I.