APP Anterograde Transport Requires Rab3A GTPase Activity for Assembly of the Transport Vesicle

• DOI: 10.1523/jneurosci.1546-09.2009
• Publication Date: 2009-11-19T00:01:28Z
• Authors: Anita Szodorai; Yung-Hui Kuan; Silke Hunzelmann; Ulrike Engel; Ayuko Sakane; Takuya Sasaki; Yoshimi Takai; Joachim Kirsch; Ulrike Müller; Konrad Beyreuther; Scott Brady; Gerardo Morfini; Stefan Kins
• Keywords: Mice, Knockout; 0301 basic medicine; Base Sequence; Molecular Sequence Data; 2800 General Neuroscience; Kinesins; 610 Medicine & health; 11359 Institute for Regenerative Medicine (IREM); rab3A GTP-Binding Protein; GTP Phosphohydrolases; 3. Good health; Enzyme Activation; Mice, Inbred C57BL; Amyloid beta-Protein Precursor; Mice; Protein Transport; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Transport Vesicles

The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by β- and γ-secretases leading to accumulation of β-amyloid (Aβ) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by α-secretases prevents Aβ generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP in transport vesicles by α-secretase activity, likely mediated by ADAM10. Together, these data indicate that maturation of APP transport vesicles, including recruitment of conventional kinesin, requires Rab3 GTPase activity.