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 A beta1-43 in the absence of N2 supplement, but could not inhibit AP secretion from NL-APP, HN could also protect neuronal cells from death by NL-APP lacking the 41st and 42nd residues of the A beta region, Therefore, HN suppressed neuronal cell death by NL-APP not through inhibition of A beta 42 secretion, but with two targets for its inhibitory action: (i) the intracellular toxic mechanism directly triggered by NL-APP and (ii) neurotoxicity by A beta. HN will contribute to the development of curative therapy of AD, especially as a novel reagent that could mechanistically supplement A beta -production inhibitors.