Axonal amyloid precursor protein and its fragments undergo somatodendritic endocytosis and processing

作者：Niederst Emily D; Reyna Sol M; Goldstein Lawrence S B^*

来源：Molecular Biology of the Cell, 2015, 26(2): 205-217.

DOI：10.1091/mbc.E14-06-1049

Deposition of potentially neurotoxic A beta fragments derived from amyloid precursor protein (APP) at synapses may be a key contributor to Alzheimer's disease. However, the location(s) of proteolytic processing and subsequent secretion of APP fragments from highly compartmentalized, euploid neurons that express APP and processing enzymes at normal levels is not well understood. To probe the behavior of endogenous APP, particularly in human neurons, we developed a system using neurons differentiated from human embryonic stem cells, cultured in microfluidic devices, to enable direct biochemical measurements from axons. Using human or mouse neurons in these devices, we measured levels of A beta, sAPP alpha, and sAPP beta secreted solely from axons. We found that a majority of the fragments secreted from axons were processed in the soma, and many were dependent on somatic endocytosis for axonal secretion. We also observed that APP and the beta-site APP cleaving enzyme were, for the most part, not dependent on endocytosis for axonal entry. These data establish that axonal entry and secretion of APP and its proteolytic processing products traverse different pathways in the somatodendritic compartment before axonal entry.

• 出版日期2015-1-15