期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 46, 页码 14534-14544出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1546-09.2009
关键词
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资金
- Deutsche Forschungsgemeinschaft
- Fritz-Thyssen Stiftung
- Alzheimer Forschung Initiative
- National Institute of Neurological Disorders and Stroke [NS23868, NS23320, NS41170, NS43408]
- MDA
- ALS Association
- American Parkinson's Disease Association
- Huntington's Disease Society of America
- Grants-in-Aid for Scientific Research [21390082] Funding Source: KAKEN
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 beta- and gamma-secretases leading to accumulation of beta-amyloid (A beta) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by alpha-secretases prevents A beta 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 alpha-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.
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