Summary
The plasma membranes of many cell types, such as epithelial cell and neurons, are polarized into distinct domains. In epithelial cells, we have found, that the targeting of newly synthesized membrane proteins is governed largely by a ubiquitously distributed set of cytoplasmic domain sorting signals. These determinants may be superficially related to well-characterized signals for localization at plasma membrane-coated pits. Their inactivation results in transport to the apical surface by a second targeting determinant found in the extracellular and/or membrane-anchoring domains. Importantly, these sorting signals are recognized in both be Golgi complex and in endosomes, indicating that a common mechanism is responsible for polarized sorting of both newly synthesized proteins and proteins internalized by endocytosis. The Alzheimer’s amyloid precursor protein (APP) is expressed by polarized cell types such as endothelial and neuronal cells. Thus, we analyzed its intracellular transport in the MDCK kidney epithelial cell line and asked whether mutations in the APP gene that lead to familial early onset Alzheimer’s disease have any effect on the polarity of APP transport or the release of amyloidogenic fragments. Wild type APP is transported to the basolateral surface due to a basolateral targeting signal in its cytoplasmic domain. While both the α-cleaved soluble APPs and amyloidogenic Aβ fragments are released into the basolateral medium, β-cleaved APPs is released apically. Removal of the APP cytoplasmic domain results in apical secretion of the Aβ fragment. Thus, Aβ release but not β-APPs release follows the polarity of the membrane-bound precursor, suggesting that β-cleavage occurs in the Golgi prior to polarized sorting of APP whereas the γ-cleavage responsible for Aβ release occurs after sorting at either the apical or basolateral domains. While the Swedish FAD mutation has no effect on polarity of APP transport, mutations affecting position 717 in the membrane-anchoring domain appear to alter the polarity of release of APP cleavage products. This finding suggests that polarity of Aβ release may be a contributing factor in the pathogenesis of Alzheimer’s disease.
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© 1995 Springer-Verlag Berlin Heidelberg
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Mellman, I. et al. (1995). Mechanisms of Molecular Sorting in Polarized Cells: Relevance to Alzheimer’s Disease. In: Kosik, K.S., Selkoe, D.J., Christen, Y. (eds) Alzheimer’s Disease: Lessons from Cell Biology. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79423-0_2
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DOI: https://doi.org/10.1007/978-3-642-79423-0_2
Publisher Name: Springer, Berlin, Heidelberg
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