Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein.
We report a novel gene, designated Humanin (HN) cDNA, that suppresses neuronal cell death by K595N/M596L-APP (NL-APP), a mutant causing familial Alzheimer's disease (FAD), termed Swedish mutant. Transfection of neuronal cells with HN cDNA or treatment with the coding HN polypeptide abrogated cytotoxicity by NL-APP. HN suppressed neurotoxicity by Abeta1-43 in the absence of N2 supplement, but could not inhibit Abeta secretion from NL-APP. HN could also protect neuronal cells from death by NL-APP lacking the 41st and 42nd residues of the Abeta region. Therefore, HN suppressed neuronal cell death by NL-APP not through inhibition of Abeta42 secretion, but with two targets for its inhibitory action: (i) the intracellular toxic mechanism directly triggered by NL-APP and (ii) neurotoxicity by Abeta. HN will contribute to the development of curative therapy of AD, especially as a novel reagent that could mechanistically supplement Abeta-production inhibitors.
Hashimoto
Y
Y
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Ito
Y
Y
Niikura
T
T
Shao
Z
Z
Hata
M
M
Oyama
F
F
Nishimoto
I
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D013548:Sweden; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011506:Proteins; C427211:humanin