The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport

Alcadein alpha (Alc alpha) is an evolutionarily conserved type I membrane protein expressed in neurons. We show here that Alca strongly associates with kinesin light chain (K-D approximate to 4-8 x 10(-9) M) through a novel tryptophan- and aspartic acid-containing sequence. Alc alpha can induce kinesin-1 association with vesicles and functions as a novel cargo in axonal anterograde transport. JNK-interacting protein 1 (JIP1), an adaptor protein for kinesin-1, perturbs the transport of Alca, and the kinesin-1 motor complex dissociates from Alc alpha-containing vesicles in a JIP1 concentration-dependent manner. Alc alpha-containing vesicles were transported with a velocity different from that of amyloid beta-protein precursor (APP)-containing vesicles, which are transported by the same kinesin-1 motor. Alc alpha- and APP-containing vesicles comprised mostly separate populations in axons in vivo. Interactions of Alca with kinesin-1 blocked transport of APP-containing vesicles and increased beta-amyloid generation. Inappropriate interactions of Alc- and APP-containing vesicles with kinesin-1 may promote aberrant APP metabolism in Alzheimer's disease.