["Death and survival of neuronal cells exposed to Alzheimer's disease-relevant insults"].
The mechanism for neuronal cell death by familial Alzheimer's disease (FAD) genes turned out to consist of various elemental combinations by the different types of cytotoxicity. We therefore tried a new approach toward identifying novel anti-AD suppressors of neuronal death, termed disease-based death trap screening. The identified genes were classified into three categories. In the first category, there were known anti-cell death genes; in the second, there were known genes with unknown function; and in the third, there were novel genes. The cDNA that encodes a 24-residue peptide, termed HN, is in the third category. HN protects neuronal death caused not only by all known kinds of FAD genes (mutant APP, PS1 and PS2), but also by anti-APP antibody and Abeta peptides, but not by long polyQ or SOD1 mutants. HN is a secretory peptide and exerts its protective function from the outside of the cell. The function of HN strictly depends on the structure. C8A-HN lost the activity and S14G-HN had approximately 1000 times increased potency of its action. Immunoblot analysis detected 3-kDa HN immunoreactive peptide in the testis and the colon in 3-week-old mice and only in the testis in 12-week-old mice. Notably, no HN immunoreactivity was detected in the brain. However, in an AD brain, not in an age-matched control, HN immunoreactivity was detected in neurons in the occipital lobe and in reactive glias in the hippocampal sections. The specific binding for HN exists on the neuronal cells and the rescue action of HN is specifically inhibited by genistein but not by wortmannin, suggesting that HN acts through the neuronal surface receptor linked to certain tyrosine kinases, but different from typical receptor tyrosine kinases. This study will provide a new insight into the research of AD.
Nishimoto
Ikuo
I
Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000166:cytology*; D016923:Cell Death; D002470:Cell Survival; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009474:Neurons; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C427211:humanin; D011505:Protein-Tyrosine Kinases