Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor

• Published in: Nature (London) 1992-09, Vol.359 (6390), p.64-67
• Main Authors: Yoshikawa, Kazuaki, Aizawa, Takako, Hayashi, Yokichi
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - biosynthesis; Brain; Humanities and Social Sciences; Humans; letter; Medical research; Mitosis; multidisciplinary; Nerve Degeneration - physiology; Neurons - cytology; Neurons - metabolism; Neurons - pathology; Proteins; Science; Science (multidisciplinary); Transfection; Tumor Cells, Cultured
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/359064a0

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 protein 1,2 , 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 acid 4–6 . 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.