beta-amyloid precursor protein can be transported independent of any sorting signal to the axonal and dendritic compartment.
In neurons, amyloid precursor protein (APP) is localized to the dendritic and axonal compartment. Changes in subcellular localization affect secretase cleavage of APP, altering the generation of Abeta, and presumably also its pathogenic features. It was reported that APP is sorted initially to the axon and transcytosed subsequently to the somatodendritic compartment. This may be carried out by a recessive dendritic sorting signal in the cytoplasmic C-terminus, possibly the tyrosine based basolateral sorting signal (BaSS), and an axonal sorting motif within the extracellular juxtamembraneous domain. We investigated whether the C- or N-terminal domain of APP contains an independent dendritic or axonal sorting signal. We generated different APP deletion mutants, and produced chimeric proteins of APP and a non-related Type I transmembrane protein. Quantitative immunocytochemical analyses of transfected primary neurons showed that similar amounts of all APP mutants, lacking either the N- or C-terminus, were transported to the axonal and dendritic compartment. Investigations of the chimeric proteins showed that neither the N- nor the C-terminus of APP functions as independent sorting signal, whereas another tyrosine based dendritic sorting signal was sufficient to prevent axonal entry of APP. This data shows that, under steady state conditions, Heterologously expressed APP is transported equally to axons and dendrites irrespective of any putative sorting signal in its N- or C-terminus. This shows that APP can enter the axon in absence of the initial axonal sorting motif, indicating the existence of an alternative pathway allowing axonal entry of APP.
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Simone
S
Zentrum für Molekulare Biologie Heidelberg (ZMBH), Germany.
Haas
Petra
P
Tschäpe
Jakob-A
JA
Gruebl
Tomas
T
Kirsch
Joachim
J
Müller
Ulrike
U
Beyreuther
Konrad
K
Kins
Stefan
S
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins; D009474:Neurons / Q000166:cytology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D017384:Sequence Deletion / Q000502:physiology; D014162:Transfection / Q000379:methods
D016564:Amyloid beta-Protein Precursor; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse