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Understanding the intracellular transport of the ␤-amyloid precursor protein (APP) is a major key to elucidate the regulation of APP processing and thus ␤-amyloid peptide generation in Alzheimer disease pathogenesis. APP and its two paralogues, APLP1 and APLP2 (APLPs), are processed in a very similar manner by the same protease activities. A putative candidate involved in APP transport is protein interacting with APP tail 1 (PAT1), which was reported to interact with the APP intracellular domain. We show that PAT1a, which is 99.0% identical to PAT1, binds to APP, APLP1, and APLP2 in vivo and describe their co-localization in trans-Golgi network vesicles or endosomes in primary neurons. We further demonstrate a direct interaction of PAT1a with the basolateral sorting signal of APP/APLPs. Moreover, we provide evidence for a direct role of PAT1a in APP/APLP transport as overexpression or RNA interference-mediated knockdown of PAT1a modulates APP/APLPs levels at the cell surface. Finally, we show that PAT1a promotes APP/APLPs processing, resulting in increased secretion of ␤-amyloid peptide. Taken together, our data establish PAT1a as a functional link between APP/APLPs transport and their processing.Amyloid plaques, the major hallmark of Alzheimer disease, are mainly composed of the ␤-amyloid peptide (A␤), 6 which is proteolytically derived from the ␤-amyloid precursor protein (APP) (1). APP belongs to a protein family with two mammalian paralogues, the ␤-amyloid precursor-like proteins (APLP) 1 and 2 (2-5). APP/APLPs share highly conserved protein domain organization (6), form homo-and heterotypic interactions (7), and are proteolytically processed in a similar manner (8). The extracellular domain of APP/APLPs can be cleaved by ␣-secretases or, alternatively, by the ␤-secretase ␤-site APP cleaving enzyme 1 (BACE 1) (8 -12). The resulting membraneretained C-terminal fragments (CTFs) are subsequently processed by cleavage within the transmembrane domain by the ␥-secretase complex (13,14). Consecutive ␤-and ␥-cleavage of APP/APLPs results in the release of A␤/A␤-like peptides, whereas ␣-and ␥-cleavage generate p3/p3-like fragments, respectively. Concomitantly, both processing pathways liberate the corresponding intracellular domains (ICDs) (8,15,16). A function in nuclear signaling was proposed for the APP/APLP ICDs (16 -18), suggesting that processing of APP/APLPs is a crucial step in the pathology of Alzheimer disease and central to the physiological function of APP/APLPs.For APP, a number of intracellular interaction partners, such as Fe65 (19), Fe65L1 (20), or X11␣ and X11␤ (21), are known to affect its processing. All of these proteins interact with the NPTY motif in the intracellular domain of APP, APLP1, and APLP2 via their phosphotyrosine binding (PTB) domain (22). Protein interacting with APP tail 1 (PAT1) binds to the basolateral sorting sequence (BaSS) of APP and is associated with microtubules. Further, an influence on APP cleavage at the cell surface has been proposed (23). Therefore, a kinesin light cha...

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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