期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 9, 页码 2386-2395出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3089-04.2005
关键词
APP; presenilin; kinesin-1; axonal transport; Alzheimer's disease; proteolysis
资金
- NIA NIH HHS [AG11542, P01 AG011542, AG05146, AG-021494, R01 AG021494, P50 AG005146] Funding Source: Medline
- NINDS NIH HHS [R01 NS041438, R01 NS041170, NS43408, R01 NS045150, R01 NS023868, R56 NS023868, R01 NS023320, NS41170, NS45150, R01 NS043408, NS41438, NS23868, NS23320] Funding Source: Medline
The sequential enzymatic actions of beta-APP cleaving enzyme 1 ( BACE1), presenilins ( PS), and other proteins of the gamma-secretase complex liberate beta-amyloid (Abeta) peptides from larger integral membrane proteins, termed beta-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment( s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a kinesin-1 cargo receptor and that PS and BACE1 are associated with the APP-resident membranous cargos that undergo rapid axonal transport. In this report, derived from a collaboration among several independent laboratories, we examined the potential associations of APP and kinesin-1 using glutathione S-transferase pull-down and coimmunoprecipitation assays. In addition, we assessed the trafficking of membrane proteins in the sciatic nerves of transgenic mice with heterozygous or homozygous deletions of APP. In contrast to previous reports, we were unable to find evidence for direct interactions between APP and kinesin-1. Furthermore, the transport of kinesin-1 and tyrosine kinase receptors, previously reported to require APP, was unchanged in axons of APP-deficient mice. Finally, we show that two components of the APP proteolytic machinery, i.e., PS1 and BACE1, are not cotransported with APP in the sciatic nerves of mice. These findings suggest that the hypothesis that APP serves as a kinesin-1 receptor and that the proteolytic processing machinery responsible for generating Abeta is transported in the same vesicular compartment in axons of peripheral nerves requires revision.
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