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

A novel factor, termed Humanin (HN), antagonizes against neurotoxicity by various types of familial Alzheimer's disease (AD) genes [V6421 and K595N/M596L (NL) mutants of amyloid precursor protein (APP), M146L-presenilin (PS) 1, and N1411-PS2] and by Aβ1-43 with clear action specificity ineffective on neurotoxicity by polyglutamine repeat Q79 or superoxide dismutase 1 mutants. Here we report that HN can also inhibit neurotoxicity by other AD-relevant insults: other familial AD genes (A617G-APP, L648P-APP, A246E-PS1, L286V-PS1, C410Y-PS1, and H163R-PS1), APP stimulation by anti-APP antibody, and other Aβ peptides (Aβ1-42 and Aβ25-35). The action specificity was further indicated by the finding that HN could not suppress neurotoxicity by glutamate or prion fragment. Against the AD-relevant insults, essential roles of Cys⁸ and Ser¹⁴ were commonly indicated, and the domain from Pro³ to Pro¹⁹ was responsible for the rescue action of HN, in which seven residues turned out to be essential. We also compared the neuroprotective action of S14G HN (HNG) with that of activity-dependent neurotrophic factor, IGF-1, or basic FGF for the antagonism against various AD-relevant insults (V6421-APP, NL-APP, M146L-PS1, N1411-PS2, and Aβ1-43). Although all of these factors could abolish neurotoxicity by Aβ1-43, only HNG could abolish cytotoxicities by all of them. HN and HN derivative peptides may 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.