Generation of amyloidogenic C-terminal fragments during rapid axonal transport in vivo of beta-amyloid precursor protein in the optic nerve

Abstract

The amyloid beta-protein (A beta) is a major component of extracellular deposits that are characteristic features of Alzheimer's disease. A beta is derived from the large transmembrane beta-amyloid precursor protein (beta APP). In the rabbit optic nerve/optic tract (ON), beta APP is synthesized in vivo in retinal ganglion cell perikarya, rapidly transported into the ON axons in small transport vesicles and is subsequently transferred to the axonal plasma membrane as well as to the presynaptic nerve terminals (Morin, P. J., Abraham, C. R., Amaratunga, A., Johnson, R.J., Huber, G., Sandell, J. H., and Fine, R. E. (1993) J. Neurochem. 61, 464-473). Present results indicate that there is rapid processing of beta APP in the ON to generate a 14-kDa C-terminal membrane-associated fragment that contains the A beta sequence. By using equilibrium sucrose density gradient fractionation, this fragment, as well as non-amyloidogenic C-terminal fragments and intact beta APP, are detected in at least two classes of transport vesicles destined for the plasma membrane and the presynaptic nerve terminal. The two classes of transported vesicles are distinguished by labeling kinetics as well as by density. In contrast to the ON, only nonamyloidogenic C-terminal fragments are generated in the retina, which contains the perikarya of retinal ganglion cells and glial (Muller) cells which also produce beta APP.