Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited.
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.
Lazarov
Orly
O
Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Chicago, Illinois 60637, USA.
Morfini
Gerardo A
GA
Lee
Edward B
EB
Farah
Mohamed H
MH
Szodorai
Anita
A
DeBoer
Scott R
SR
Koliatsos
Vassilis E
VE
Kins
Stefan
S
Lee
Virginia M-Y
VM
Wong
Philip C
PC
Price
Donald L
DL
Brady
Scott T
ST
Sisodia
Sangram S
SS
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001369:Axons / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003001:Cloning, Molecular / Q000379:methods; D010450:Endopeptidases / Q000172:deficiency; D015870:Gene Expression / Q000502:physiology; D005982:Glutathione Transferase / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation / Q000379:methods; D016547:Kinesins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology; D020426:Sciatic Neuropathy / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D020794:Receptor Protein-Tyrosine Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D016547:Kinesins
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