Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor.
A pathological hallmark of Alzheimer's disease is the deposition of amyloid fibrils in the brain. The principal component of amyloid fibrils is beta/A4 amyloid protein, which can be generated by the aberrant processing of a large membrane-bound glycoprotein, the beta/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. When differentiation of the APP cDNA-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 beta/A4 domain. These results suggest that post-mitotic neurons are vulnerable to overexpressed APP, which undergoes aberrant processing to generate potentially amyloidogenic fragments.
Yoshikawa
K
K
Department of Molecular Biology, Tokyo Institute of Psychiatry, Japan.
Aizawa
T
T
Hayashi
Y
Y
D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D006801:Humans; D008938:Mitosis; D009410:Nerve Degeneration / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor