INTRACELLULAR ROUTING OF HUMAN AMYLOID PROTEIN-PRECURSOR - AXONAL DELIVERY FOLLOWED BY TRANSPORT TO THE DENDRITES

A characteristic neuropathological feature of Alzheimer's disease is t he cerebral deposition of amyloid plaques, These deposits contain beta A4 amyloid peptide, a cleavage product of the transmembrane protein a myloid protein precursor (APP), Despite numerous studies on the proces sing of the different APP isoforms in non-neuronal cells, little is kn own about its sorting and transport in neurons of the central nervous system (CNS), To analyze this question we expressed in cultured rat hi ppocampal neurons the human APP 695, tagged at its N-terminus with the myc epitope, using the Semliki forest virus (SFV) expression system, APP was first delivered from the cell body to the axon and later appea red also in the dendrites, Inhibition of protein synthesis at the time of axonal expression did not block the late appearance of the protein in the dendrites, An antibody directed against the myc tag, bound to the cell surface at 4 degrees C at the time of axonal APP expression, could be chased to the dendritic domain after subsequent incubation at 37 degrees C. These results suggest that the newly synthesized APP, a fter initial axonal delivery, may be transported to the dendrites by a transcytotic mechanism, The routing of APP in polarized neurons is di fferent from that of polarized epithelial cells, in which the protein is delivered basolaterally, arguing for neuronal specific sorting and processing mechanisms. (C) 1995 Wiley-Liss, Inc.