Detailed Characterization of Neuroprotection by a Rescue Factor Humanin against Various Alzheimer's Disease-Relevant Insults

Abstract

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 (A␤1-42 and A␤25-35). 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 Cys 8 and Ser 14 were commonly indicated, and the domain from 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 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 A␤1-43). Although all of these factors could abolish neurotoxicity by A␤1-43, 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.

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

“…It was therefore reasonable to assume that a soluble rescue factor is secreted from hGtx-transfected cells. We have shown so far that IGF-I inhibits apoptotic neuronal cell death by V642I-A␤PP (48) and does not affect DEVDresistant cell death by NL-A␤PP, N141I-PS2, or M141L-PS1 (22). As shown in Fig.…”

“…These data indicate, again, that hGtx suppresses caspase inhibitor-sensitive apoptotic neuronal cell death by V642I-A␤PP, which concurs with the notion that hGtx effectively suppresses the apoptotic component of neurotoxicity by FAD mutants of A␤PP. (38), both of which have been shown to cause neuronal cell death in vitro (22,38). By using the 1.5-g protocol allowing for overexpression of FAD genes, we examined the effect of hGtx on neuronal cell death by A617G-A␤PP and by L648P-A␤PP.…”

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

“…Although the neuroprotective effects of HN are now well known [21,41] and have been confi rmed in transgenic AD mice [42] , the intrinsic mechanisms by which it suppresses AD-like pathological changes and memory deficits in vivo are still unclear. In the present study, we showed that HN ameliorated the Aβ 1-42 -induced spatial memory defi ciency by reversing LTP impairment, synaptic dysfunction, dendritic degeneration, neuronal apoptosis, oxidative stress, and tau hyperphosphorylation.…”

“…HN suppresses the neurotoxicity of various causative genes for familial AD (FAD) including FAD-related mutant PS1 and PS2 genes [17][18][19] , and inhibits the neuronal cell death caused by Aβ [20,21] . HN is also effective against cell death caused by non-AD-related insults, such as serum deprivation, prion peptide 118-135, and insulin-like growth factor binding protein 3 [22][23][24] .…”

Construction of a eukaryotic expression plasmid of Humanin

“…The mutation of the peptides may increase β-amyloid (Aβ) level and further extracellular deposits of Aβ, which forms the amyloid plaque and leads to the death of neurocytes. Hashimoto et al(2001b;2001c) reported that a short peptide, named Humanin, was isolated from the brain of AD patients. Humanin had significant protective action on the neurocytes death induced by APP, PS1, PS2 and Aβ.…”