A femtomolar-acting neuroprotective peptide.

Brenneman, Douglas E.; Gozes, Illana

doi:10.1172/jci118672

Cited by 247 publications

(216 citation statements)

References 62 publications

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“…One to 100 fM ADNF, 100 pM to 1 nM IGF-I, 1-10 nM bFGF, and 1-10 nM HNG suppressed neuronal death by A␤1-43 to the levels of basal cell death, indicating that these factors selectively abolish neurotoxicity by A␤ without affecting basally occurring death. Higher concentrations of IGF-I, bFGF, and HNG exerted complete neuroprotection, whereas Ն100 nM concentrations of ADNF lost its neuroprotective activity, as repeatedly reported in the literature (Brenneman and Gozes, 1996;Brenneman et al, 1998;Glazner et al, 1999). Although it remains unknown why the full action of ADNF was only observed at high femtomolar to low picomolar concentrations, such a phenomenon was not attributed to potential combination of its rescue action by low concentrations and its toxic action by higher concentrations, because ADNF alone was not neurotoxic, even at 100 nM (data not shown).…”

Section: Comparison Of the Action Of Hng With Those Of Adnf Igf-i Asupporting

confidence: 80%

“…Although each of ADNF, IGF-I, and bFGF could suppress neurotoxicity induced by A␤, as shown by previous studies (Brenneman and Gozes, 1996;Dore et al, 1997;Mark et al, 1997;Brenneman et al, 1998), ADNF, IGF-I, and bFGF only inhibited V642I-APP-induced cytotoxicity and could not affect neuronal cell death by mutant PS1 and PS2. In contrast, HN and HNG suppressed the neurotoxicities by mutants of APP, PS1, and PS2, which are all known FAD genes.…”

Section: Discussionmentioning

confidence: 57%

“…Among known neurotrophic factors, ADNF (Brenneman and Gozes, 1996;Brenneman et al, 1998;, bFGF (Mark et al, 1997), and IGF-I (Dore et al, 1997) are known to suppress neurotoxicity by A␤ at femtomolar, low nanomolar, and high nanomolar concentrations, respectively, although ADNF cannot exert neuroprotection at concentrations higher than 100 pM. Here, we investigated whether and how these factors and HNG antagonize against neuronal cell death caused by the four representative FAD genes: V642I-APP, NL-APP, M146L-PS1, and N141I-PS2.…”

Section: Comparison Of the Action Of Hng With Those Of Adnf Igf-i Amentioning

confidence: 99%

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

et al. 2001

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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.

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Section: Comparison Of the Action Of Hng With Those Of Adnf Igf-i Asupporting

confidence: 80%

Section: Discussionmentioning

confidence: 57%

Section: Comparison Of the Action Of Hng With Those Of Adnf Igf-i Amentioning

confidence: 99%

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

et al. 2001

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“…ADNP mRNA is regulated by VIP (Bassan et al, 1999), and here we demonstrate that incubation with VIP resulted in higher levels of ADNP-like immunoreactivity in conditioned media from astrocytes. VIP is known to produce a neurotrophic milieu (Brenneman et al, 1990;Gozes et al, 1991;Waschek, 1995;Brenneman and Gozes, 1996;Gressens, 1999;Brenneman et al, 2003), and it has been suggested that ADNP constitutes part of this protective environment. However, it is unclear whether ADNP is released into the medium by a constitutive or regulated process.…”

Section: Discussionmentioning

confidence: 99%

Subcellular localization and secretion of activity-dependent neuroprotective protein in astrocytes

et al. 2004

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Activity-dependent neuroprotective protein (ADNP, ∼123562.8 Da), is synthesized in astrocytes and expression of ADNP mRNA is regulated by the neuroprotective peptide vasoactive intestinal peptide (VIP). The gene that encodes ADNP is conserved in human, rat and mouse, and contains a homeobox domain profile that includes a nuclear-export signal and a nuclear-localization signal. ADNP is essential for embryonic brain development, and NAP, an eight-amino acid peptide that is derived from ADNP, confers potent neuroprotection. Here, we investigate the subcellular localization of ADNP through cell fractionation, gel electrophoresis, immunoblotting and immunocytochemistry using α-CNAP, an antibody directed to the neuroprotective NAP fragment that constitutes part of an N-terminal epitope of ADNP. Recombinant ADNP was used as a competitive ligand to measure antibody specificity. ADNP-like immunoreactivity was found in the nuclear cell fraction of astrocytes and in the cytoplasm. In the cytoplasm, ADNP-like immunoreactivity colocalized with tubulin-like immunoreactivity and with microtubular structures, but not with actin microfilaments. Because microtubules are key components of developing neurons and brain, possible interaction between tubulin and ADNP might indicate a functional correlate to the role of ADNP in the brain. In addition, ADNP-like immunoreactivity in the extracellular milieu of astrocytes increased by ∼1.4 fold after incubation of the astrocytes with VIP. VIP is known to cause astrocytes to secrete neuroprotective/ neurotrophic factors, and we suggest that ADNP constitutes part of this VIP-stimulated protective milieu.

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“…Colivelin (CLN), the strongest HN derivative so far developed, is a fusion peptide composed of a potent HN derivative named AGA-(C8R)HNG17 attached to the C terminus of activitydependent neurotrophic factor (ADNF) (Brenneman and Gozes, 1996;Brenneman et al, 1998;Chiba et al, 2004Chiba et al, , 2005Chiba et al, , 2006Matsuoka et al, 2006). Our earlier studies indicated that HN and CLN suppressed AD-relevant neuronal death by activating STAT3 in vitro Hashimoto et al, 2005;Matsuoka et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Yamada

Chiba

Sasabe

et al. 2007

Neuropsychopharmacol

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Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-b (Ab) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Ab induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

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A femtomolar-acting neuroprotective peptide.

Abstract: Abstract

Cited by 247 publications

References 62 publications

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

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

Subcellular localization and secretion of activity-dependent neuroprotective protein in astrocytes

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

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