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The Journal of Neuroscience, December 1, 2001, 21(23):9235-9245
Detailed Characterization of Neuroprotection by a Rescue Factor
Humanin against Various Alzheimer's Disease-Relevant Insults
Yuichi
Hashimoto,
Takako
Niikura,
Yuko
Ito,
Haruka
Sudo,
Michihiro
Hata,
Erika
Arakawa,
Yoichiro
Abe,
Yoshiko
Kita, and
Ikuo
Nishimoto
Department of Pharmacology and Neurosciences, Keio University
School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
A novel factor, termed Humanin (HN), antagonizes against
neurotoxicity by various types of familial Alzheimer's disease (AD) genes [V642I and K595N/M596L (NL) mutants of amyloid precursor protein
(APP), M146L-presenilin (PS) 1, and N141I-PS2] and by A 1-43
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 A peptides (A1-42 and A25-35). 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-I, or basic
FGF for the antagonism against various AD-relevant insults (V642I-APP,
NL-APP, M146L-PS1, N141I-PS2, and A1-43). Although all of these
factors could abolish neurotoxicity by A1-43, 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.
Key words:
Keyword: Humanin; neuronal cell death; rescue; Alzheimer's disease; mutant; A
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239235-11$05.00/0
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