Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling.
We recently demonstrated that the Alzheimer's beta-amyloid precursor protein (APP) is internalized from the axonal cell surface. In this study, we use biochemical and cell biological methods to characterize endocytotic compartments that participate in trafficking of APP in central neurons. APP is present in presynaptic clathrin-coated vesicles purified from bovine brain, together with the recycling synaptic vesicle integral membrane proteins synaptophysin, synaptotagmin, and SV2. In contrast, APP is largely excluded from synaptic vesicles purified from rat brain. In primary cerebellar macroneurons, cell-surface APP is internalized with recycling synaptic vesicle integral membrane proteins but is subsequently sorted away from synaptic vesicles and transported retrogradely to the neuronal soma. Internalized APP partially co-localizes with rab5a-containing compartments in axons and with V-ATPase-containing compartments in both axons and neuronal soma. These results provide direct biochemical evidence that an obligate sorting compartment participates in the regeneration of synaptic vesicles during exo/endocytotic recycling at nerve terminals but do not preclude concurrent "kiss-and-run" recycling. Moreover, APP is now, to our knowledge, the first demonstrated example of an axonal cell-surface protein that is internalized with recycling synaptic vesicle membrane proteins but is subsequently sorted away from synaptic vesicles.
Marquez-Sterling
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Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
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Sisodia
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Koo
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D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002462:Cell Membrane; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D018699:Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats / Q000196:embryology; D013572:Synaptic Vesicles / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D002966:Clathrin; D008565:Membrane Proteins