Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults

novel factor, termed Humanin (HN), antagonizes against neurotoxicity by var ious types of familial Alzheimer's disease (AD) genes [V642I and K595N/M596 L (NL) mutants of amyloid precursor protein (APP), M146L-presenilin (PS) 1, and N141I-PS2] and by A beta1-43 with clear action specificity ineffective on neurotoxicity by polyglutamine repeat Q79 or superoxide dismutase 1 mut ants. Here we report that HN can also inhibit neurotoxicity by other AD-rel evant insults: other familial AD genes (A617G-APP, L648P-APP, A246E-PS1, L2 86V-PS1, C410Y-PS1, and H163R-PS1), APP stimulation by anti-APP antibody, a nd other A beta peptides (A beta1-42 and A beta 25-35). The action specific ity was further indicated by the finding that HN could not suppress neuroto xicity by glutamate or prion fragment. Against the AD-relevant insults, ess ential roles of Cys 8 and Ser(14) were commonly indicated, and the domain f rom Pro(3) to Pro(19) was responsible for the rescue action of HN, in which seven residues turned out to be essential. We also compared the neuroprote ctive action of S14G HN (HNG) with that of activity-dependent neurotrophic factor, IGF-I, or basic FGF for the antagonism against various AD-relevant insults (V642I-APP, NL-APP, M146L-PS1, N141I-PS2, and A beta1-43). Although all of these factors could abolish neurotoxicity by A beta -43, only HNG c ould abolish cytotoxicities by all of them. HN and HN derivative peptides m ay provide a new insight into the study of AD pathophysiology and allow new avenues for the development of therapeutic interventions for various forms of AD.