colivelin and humanin

Topics: Alzheimer Disease; Animals; Drug Design; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; Nerve Tissue Proteins; STAT3 Transcription Factor; Synaptic Transmission

Neuronal death is directly implicated in the pathogenesis of neurodegenerative diseases (NDDs). NDDs cannot be cured because the mechanisms underlying neuronal death are too complicated to be therapeutically suppressed. Neuroprotective factors, such as neurotrophins, certain growth factors, neurotrophic cytokines, and short neuroprotective peptides, support neuronal survival in both physiological and pathological conditions, suggesting that these factors may be good drug candidates for NDDs. We recently generated a novel neuroprotective peptide named Colivelin by attaching activity-dependent neurotrophic factor (ADNF) to the N-terminus of a potent Humanin derivative, AGA-(C8R)HNG17. HN was originally identified from an Alzheimer's disease (AD) brain as an endogenous neuroprotective peptide that suppresses ADrelevant toxicity. Colivelin protects neurons from death relevant to NDDs by activating two independent prosurvival signals: an ADNF-mediated Ca2+/calmodulin-dependent protein kinase IV pathway and an HN-mediated STAT3 pathway. The neuroprotective effect of Colivelin provides novel insights into therapy for NDDs.

Topics: Amino Acid Sequence; Animals; Apoptosis; Cytokines; Humans; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Molecular Sequence Data; Nerve Growth Factors; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Peptides; Recombinant Fusion Proteins; Sequence Alignment; Signal Transduction

Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 10(5) times more potent as a neuroprotective than HN; at 10-picomolar and higher concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-amino-acid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Cell Death; Humans; Intracellular Signaling Peptides and Proteins; Models, Biological

Topics: AMP-Activated Protein Kinases; Angiopoietin-2; Animals; Anti-Bacterial Agents; Endoglin; Endothelium, Vascular; Endotoxins; Glycocalyx; Intercellular Adhesion Molecule-1; Interleukin-10; Intracellular Signaling Peptides and Proteins; Macrophage Inflammatory Proteins; Male; Mice; Mice, Inbred C57BL; P-Selectin; Proprotein Convertases; Sepsis; STAT3 Transcription Factor; Subtilisins; Syndecan-1; Tumor Necrosis Factor-alpha

A 24-amino acid long peptide, Humanin, protects neurons from Alzheimer's disease (AD)-related cell toxicities at sub-nM-uM concentrations. Activity-dependent neurotrophic factor (ADNF) is a glia-derived neurotrophic peptide, which protects neurons from tetrodoxin treatment and AD-related and amyotrophic lateral sclerosis-related insults at fM concentrations. An attempt was made to further improve the activity of Humanin by fusing this peptide to ADNF9, a 9-amino acid long core peptide of the ADNF. This fusion resulted in a novel molecule, termed Colivelin, with the neuroprotective activity at fM range, which is approximately 10(3)-10(7) fold higher than the activity of Humanin and Humanin analogs and follows the activity profile of fM-active ADNF9. We have characterized the structural properties of Colivelin and compared with those of ADNF9 and Humanin in water and phosphate-buffered saline (PBS). The secondary structure of Colivelin was similar to that of ADNF9, but not that of Humanin, and hence was not the average of the contributions of the two peptides fused. Colivelin was stable and monomeric in PBS, consistent with the monomeric property of ADNF9, while Humanin showed strong tendency to self-associate. Thus, it is evident that the structural properties of Colivelin resemble those of ADNF9, rather than those of Humanin.

Topics: Amino Acid Sequence; Circular Dichroism; Drug Stability; Humans; Intracellular Signaling Peptides and Proteins; Molecular Sequence Data; Molecular Structure; Multiprotein Complexes; Nerve Tissue Proteins; Oligopeptides; Protein Structure, Secondary; Solutions; Ultracentrifugation

Alzheimer's disease (AD) is the most common cause of dementia. Humanin (HN) is a short bioactive peptide abolishing neuronal cell death induced by various familial AD (FAD)-causative genes and amyloid-beta (Abeta) in vitro. It has been shown that HN suppresses memory impairment of mice induced by intracerebroventricular administration of Abeta. To potentiate the neuroprotective effect of HN, we synthesized a hybrid peptide named Colivelin composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)HNG17, a potent HN derivative. Colivelin completely suppresses death induced by overexpressed FAD-causative genes and Abeta1-43 at a concentration of 100 fM, whereas AGA-(C8R)HNG17 does so at a concentration of 10 pM. Colivelin-induced neuroprotection has been confirmed to occur via two neuroprotective pathways: one mediated by Ca2+/calmodulin-dependent protein kinase IV, triggered by ADNF, and one mediated by signal transducer and activator of transcription 3, triggered by HN. In vivo animal studies have further indicated that intracerebroventricular administration of Colivelin not only completely suppresses impairment in spatial working memory induced by repetitive intracerebroventricular injection of Abeta25-35 or Abeta1-42, but also it antagonizes neuronal loss in the CA1 region of hippocampus induced by hippocampal injection of Abeta1-42. In addition, intraperitoneally administered Colivelin suppresses memory impairment caused by a muscarinic acetylcholine receptor antagonist, 3-quinuclidinyl benzilate, indicating that a substantial portion of intraperitoneally administered Colivelin passes through the blood-brain barrier and suppresses functional memory deficit. Thus, Colivelin might serve as a novel drug candidate for treatment of AD.

Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Cell Death; Cell Line; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Nerve Tissue Proteins; Neuroprotective Agents; Peptide Fragments; Peptides; Rats