Abstract
A PATHOLOGICAL hallmark of Alzheimer's disease is the deposition of amyloid fibrils in the brain. The principal component of amyloid fibrils is β/A4 amyloid protein1,2, which can be generated by the aberrant processing of a large membrane-bound glycoprotein, the β/A4 amyloid protein precursor (APP)3. To test whether overexpression of APP generates abnormally processed derivatives that affect the viability of neurons, we stably transfected full-length human APP complementary DNA into murine embryonal carcinoma P19 cells. These cells differentiate into post-mitotic neurons and astrocytes after exposure to retinoic acid4–6. When differentiation of the APP cDN A-transfected P19 cells was induced, all neurons showed severe degenerative changes and disappeared within a few days. The degenerating neurons contained large amounts of APP derivatives that were truncated at the amino terminus and encompassed the entire β/A4 domain. These results suggest that post-mitotic neurons are vulnerable to overexpressed APP, which undergoes aberrant processing to generate potentially amyloidogenic fragments.
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Yoshikawa, K., Aizawa, T. & Hayashi, Y. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359, 64–67 (1992). https://doi.org/10.1038/359064a0
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DOI: https://doi.org/10.1038/359064a0
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