β‐amyloid precursor protein can be transported independent of any sorting signal to the axonal and dendritic compartment

Abstract

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.

Trafficking and Proteolytic Processing of APP

“…Along this line, APP lacking the cytoplasmic domain (DC) (where the basolateral sorting signal is located; see above) is transported along neurites with characteristics indistinguishable from wild-type APP ( Fig. 7a; Back et al 2007;Szodorai et al 2009). Therefore, the basolateral sorting signal in the carboxy-terminal region of APP documented in MDCK studies seems to have no function for polarized sorting in neurons.…”

“…An axonal sorting signal was mapped to a juxtamembrane domain which includes the Ab-domain ; however, a recent report showed that APP is transported into axons and dendrites without apparent sorting signals (Back et al 2007). Along this line, APP lacking the cytoplasmic domain (DC) (where the basolateral sorting signal is located; see above) is transported along neurites with characteristics indistinguishable from wild-type APP ( Fig.…”

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

“…Two peptide sequences in the tail of APP that are important for its basolateral sorting have been identified in polarized Madin Darby canine kidney cells (a renal cell type) (De Strooper et al, 1995b;Haass et al, 1995). Apparently, axonal transport of APP in polarized neurons does not require these basolateral sorting signals, because APP mutants that lack the entire cytoplasmic tail are still sorted normally along axons and dendrites (Back et al, 2007).…”

Synaptic NMDA Receptor Activation Stimulates α-Secretase Amyloid Precursor Protein Processing and Inhibits Amyloid-β Production

“…It has recently been reported that under steady-state conditions APP is sorted equally to the axonal and somatodendritic compartment in primary neurons (Back et al, 2007). We examined the distribution pattern of endogenous APP and the trafficking of APP-GFP in primary cultured cortical neurons.…”