Skip to main content Accessibility help
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 3
  • Print publication year: 2005
  • Online publication date: August 2009

15 - Neuroendocrine Aspects of the Molecular Chaperones ADNF and ADNP

    • By Illana Gozes, Department of Clinical Biochemistry and Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Inna Vulih, Department of Clinical Biochemistry and Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Irit Spivak-Pohis, Department of Clinical Biochemistry and Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, Sharon Furman, Department of Clinical Biochemistry and Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  • Edited by Brian Henderson, University College London, A. Graham Pockley, University of Sheffield
  • Publisher: Cambridge University Press
  • DOI:
  • pp 251-262



Vasoactive intestinal peptide (VIP), which was originally discovered in the intestine as a 28–amino acid peptide and shown to induce vasodilation, was later found to be a major brain peptide with neuroprotective activities in vivo [1–5]. To exert neuroprotective activity in the brain, VIP requires glial cells that secrete protective proteins such as activity-dependent neurotrophic factor (ADNF [6]). ADNF, isolated by sequential chromatographic methods, was named activity-dependent neurotrophic factor because it protects neurons from death associated with the blockade of electrical activity.

ADNF is a 14-kDa protein, and structure-activity studies have identified femtomolar-active neuroprotective peptides, ADNF-14 (VLGGGSALLRSIPA) [6] and ADNF-9 (SALLRSIPA) [7]. ADNF-9 exhibits protective activity in Alzheimer's disease–related systems (β-amyloid toxicity [7], presenilin 1 mutation [8], apolipoprotein E deficiencies [9] – genes that have been associated with the onset and progression of Alzheimer's disease (AD)). Other studies have indicated protection against oxidative stress via the maintenance of mitochondrial function and a reduction in the accumulation of intracellular reactive oxygen species [10]. In the target neurons, ADNF-9 regulates transcriptional activation associated with neuroprotection (nuclear factor-κB [11]), promotes axonal elongation through transcriptionally regulated cAMP-dependent mechanisms [12] and increases chaperonin 60 (Cpn60/Hsp60) expression, thereby providing cellular protection against the β-amyloid peptide [13].

Longer peptides that include the ADNF-9 sequence (e.g., ADNF-14) activate protein kinase C and mitogen-associated protein kinase kinase and protect developing mouse brain against excitotoxicity [14].

Notes Added in Proof
Divinski, I, Mittelman, L and Gozes, I. A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication. J Biol Chem 2004, 279: 28531–28538
Gozes, I and Divinski, I. The femtomolar-acting NAP interacts with microtubules: Novel aspects of astrocyte protection. J Alzheimers Dis 2004, 6: S37–S41
Furman, S, Steingart, R A, Mandel, S, Hauser, J M, Brenneman, D E and Gozes, I. Subcellular localization and secretion of activity-dependent neuroprotective protein in astrocytes. Neuron Glia Biology 2005, in press
Brenneman, D E, Spong, C Y, Hauser, J M, Abebe, D, Pinhasov, A, Golian, T and Gozes, I. Protective peptides that are orally active and mechanistically nonchiral. J Pharmacol Exp Ther 2004, 309: 1190–1197
Wilkemeyer, M F, Chen, S Y, Menkari, C E, Sulik, K K and Charness, M E. Ethanol antagonist peptides: structural specificity without stereospecificity. J Pharmacol Exp Ther 2004, 309: 1183–1189
Zhou, F C, Sari, Y, Powrozek, T A and Spong, C Y. A neuroprotective peptide antagonizes fetal alcohol exposure-compromised brain growth. J Mol Neurosci 2004, 24: 189–199
Chiba, T, Hashimoto, Y, Tajima, H, Yamada, M, Kato, R, Niikura, T, Terashita, K, Schulman, H, Aiso, S, Kita, Y, Matsuoka, M and Nishimoto, I. Neuroprotective effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo. J Neurosci Res 2004, 78: 542–552
Gozes, I and Brenneman, D E.VIP: molecular biology and neurobiological function. Mol Neurobiol 1989, 3: 201–236
Gozes, I, Fridkin, M, Hill, J M and Brenneman, D E.Pharmaceutical VIP: prospects and problems. Cur Med Chem 1999, 6: 1019–1034
Gozes, I, Bardea, A, Reshef, A, Zamostiano, R, Zhukovsky, S, Rubinraut, S, Fridkin, M and Brenneman, D E.Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide. Proc Natl Acad Sci USA 1996, 93: 427–432
Gozes, I, Bachar, M, Bardea, A, Davidson, A, Rubinraut, S, Fridkin, M and Giladi, E.Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implications for early treatment of Alzheimer's disease. J Neurobiol 1997, 33: 329–342
Gozes, I, Perl, O, Giladi, E, Davidson, A, Ashur-Fabian, O, Rubinraut, S and Fridkin, M.Mapping the active site in vasoactive intestinal peptide to a core of four amino acids: neuroprotective drug design. Proc Natl Acad Sci USA 1999, 96: 4143–4148
Brenneman, D E and Gozes, I.A femtomolar-acting neuroprotective peptide. J Clin Invest 1996, 97: 2299–2307
Brenneman, D E, Hauser, J, Neale, E, Rubinraut, S, Fridkin, M, Davidson, A and Gozes, I.Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides. J Pharmacol Exp Therap 1998, 285: 619–627
Guo, Q, Sebastian, L, Sopher, B, Miller, M W, Glazner, G W, Ware, C B, Martin, G M and Mattson, M.Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc Natl Acad Sci USA 1999, 96: 4125–4130
Bassan, M, Zamostiano, R, Davidson, A, Pinhasov, A, Giladi, E, Perl, O, Bassan, H, Blat, C, Gibney, G, Glazner, G, Brenneman, D E and Gozes, I.Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 1999, 72: 1283–1293
Glazner, G W, Boland, A, Dresse, A E, Brenneman, D E, Gozes, I and Mattson, M P.Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress-induced death. J Neurochem 1999, 73: 2341–2347
Glazner, G W, Camandola, S and Mattson, M P.Nuclear factor-kappaB mediates the cell survival-promoting action of activity-dependent neurotrophic factor peptide-9. J Neurochem 2000, 75: 101–108
White, D M, Walker, S, Brenneman, D E and Gozes, I.CREB contributes to the increased neurite outgrowth of sensory neurons induced by vasoactive intestinal polypeptide and activity-dependent neurotrophic factor. Brain Res 2000, 868: 31–38
Zamostiano, R, Pinhasov, A, Bassan, M, Perl, O, Steingart, R A, Atlas, R, Brenneman, D E and Gozes, I.A femtomolar-acting neuroprotective peptide induces increased levels of heat shock protein 60 in rat cortical neurons: a potential neuroprotective mechanism. Neurosci Lett 1999, 264: 9–12
Gressens, P, Marret, S, Bodenant, C, Schwendimann, L and Evrard, P.Activity-dependent neurotrophic factor-14 requires protein kinase C and mitogen-associated protein kinase kinase activation to protect the developing mouse brain against excitotoxicity. J Mol Neurosci 1999, 13: 199–210
Guo, Z H and Mattson, M P.Neurotrophic factors protect cortical synaptic terminals against amyloid and oxidative stress-induced impairment of glucose transport, glutamate transport and mitochondrial function. Cereb Cortex 2000, 10: 50–57
Blondel, O, Collin, C, McCarran, W J, Zhu, S, Zamostiano, R, Gozes, I, Brenneman, D E and McKay, R D.A glia-derived signal regulating neuronal differentiation. J Neurosci 2000, 20: 8012–8020
Gozes, I, Giladi, E, Pinhasov, A, Golian, T, Romano, J and Brenneman, D E.Activity-dependent neurotrophic factor: comparison of intranasal and oral administration of femtomolar-acting L and D peptides to improve memory. Soc Neurosci Abstract 2000: 223
Steingart, R A, Solomon, B, Brenneman, D E, Fridkin, M and Gozes, I.VIP and peptides related to activity-dependent neurotrophic factor protect PC12 cells against oxidative stress. J Mol Neurosci 2000, 15: 137–145
Brenneman, D E, Hauser, J and Gozes, I.Synergistic and non-chiral characteristics in dissociated cerebral cortical test cultures. Soc Neurosci Abstract 2000 223–224
Gozes, I, Davidson, A, Gozes, Y, Mascolo, R, Barth, R, Warren, D, Hauser, J and Brenneman, D E.Antiserum to activity-dependent neurotrophic factor produces neuronal cell death in CNS cultures: immunological and biological specificity. Brain Res Dev Brain Res 1997, 99: 167–175
Gozes, I and Brenneman, D E.Activity-dependent neurotrophic factor (ADNF). An extracellular neuroprotective chaperonin? J Mol Neurosci 1996, 7: 235–244
Hashimoto, Y, Niikura, T, Ito, Y, Sudo, H, Hata, M, Arakawa, E, Abe, Y, Kita, Y and Nishimoto, I.Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults. J Neurosci 2001, 21: 9235–9245
Ramirez, S H, Sanchez, J F, Dimitri, C A, Gelbard, H A, Dewhurst, S and Maggirwar, S B.Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappaB (NF-kappaB)-dependent mechanism. J Neurochem 2001, 78: 874–889
Zamostiano, R, Pinhasov, A, Gelber, E, Steingart, R A, Seroussi, E, Giladi, E, Bassan, M, Wollman, Y, Eyre, H J, Mulley, J C, Brenneman, D E and Gozes, I.Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem 2001, 276: 708–714
Sigalov, E, Fridkin, M, Brenneman, D E and Gozes, I.VIP-Related protection against lodoacetate toxicity in pheochromocytoma (PC12) cells: a model for ischemic/hypoxic injury. J Mol Neurosci 2000, 15: 147–154
Offen, D, Sherki, Y, Melamed, E, Fridkin, M, Brenneman, D E and Gozes, I.Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease. Brain Res 2000, 854: 257–262
Zemlyak, I, Furman, S, Brenneman, D E and Gozes, I.A novel peptide prevents death in enriched neuronal cultures. Reg Peptides 2000, 96: 39–43
Gozes, I and Brenneman, D E.A new concept in the pharmacology of neuroprotection. J Mol Neurosci 2000, 14: 61–68
Gozes, I, Alcalay, R, Giladi, E, Pinhasov, A, Furman, S and Brenneman, D E.NAP accelerates the performance of normal rats in the water maze. J Mol Neurosci 2002, 19: 167–170
Beni-Adani, L, Gozes, I, Cohen, Y, Assaf, Y, Steingart, R A, Brenneman, D E, Eizenberg, O, Trembolver, V and Shohami, E.A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther 2001, 296: 57–63
Romano, J, Beni-Adani, L, Nissenbaum, O L, Brenneman, D E, Shohami, E and Gozes, I.A single administration of the peptide NAP induces long-term protective changes against the consequences of head injury: gene Atlas array analysis. J Mol Neurosci 2002, 18: 37–45
Spong, C Y, Abebe, D T, Gozes, I, Brenneman, D E and Hill, J M.Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome. J Pharmacol Exp Therap 2001, 297: 774–779
Newton, P E, Brenneman, D E and Gozes, I.30-day intranasal toxicity studies of NAP in rats and dogs. J Mol Neurosci 2001, 16: 61
Pelsman, A, Fernanandez, G, Gozes, I, Brenneman, D E and Busciglio, J.In vitro degeneration of Down syndrome neurons is prevented by activity-dependent neurotrophic factor-derived peptides. Soc Neurosci Abstracts 1998, 24: 1044
Leker, R R, Teichner, A, Grigoriadis, N, Ovadia, H, Brenneman, D E, Fridkin, M, Giladi, E, Romano, J and Gozes, I.NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death. Stroke 2002, 33: 1085–1092
Smith-Swintosky, V L, Gozes, I, Brenneman, D E and Plata-Salaman, C R.Activity dependent neurotrophic factor-9 and NAP promote neurite outgrowth in rat hippocampal and cortical cultures. Soc Neurosci Abstracts 2000, 26: 843
Gozes, I, Divinsky, I, Pilzer, I, Fridkin, M, Brenneman, D E and Spier, A D.From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division. J Mol Neurosci 2003, 20: 315–322
Divinski, I, Spier, A D and Gozes, I.NAP, a peptide derivative of the VIP-regulated gene ADNP, confers neuroprotection through microtubule dynamics. Reg Peptides 2003, 115: 42
Ashur-Fabian, O, Giladi, E, Furman, S, Steingart, R A, Wollman, Y, Fridkin, M, Brenneman, D E and Gozes, I.Vasoactive intestinal peptide and related molecules induce nitrite accumulation in the extracellular milieu of rat cerebral cortical cultures. Neurosci Lett 2001, 307: 167–170
Steinhoff, U, Zugel, U, Wand-Wurttenberger, A, Hengel, H, Rosch, R, Munk, M E and Kaufmann, S H E.Prevention of autoimmune lysis by T cells with specificity for a heat shock protein by antisense oligonucleotide treatment. Proc Natl Acad Sci USA 1994, 91: 5085–5088
Birk, O S, Douek, D C, Elias, D, Takacs, K, Dewchand, H, Gur, S L, Walker, M D, Zee, R, Cohen, I R and Altmann, D M.A role of hsp60 in autoimmune diabetes: analysis in a transgenic model. Proc Natl Acad Sci USA 1996, 93: 1032–1037
Kurek, J B, Bennett, T M, Bower, J J, Muldoon, C M and Austin, L.Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma. Neurosci Lett 1998, 249: 1–4
Bassan, M, Zamostiano, R, Giladi, E, Davidson, A, Wollman, Y, Pitman, J, Hauser, J, Brenneman, D E and Gozes, I.The identification of secreted heat shock 60-like protein from rat glial cells and a human neuroblastoma cell line. Neurosci Lett 1998, 250: 37–40
Hollander, J M, Lin, K M, Scott, B T and Dillmann, W H.Overexpression of PHGPⅹ and HSP60/10 protects against ischemia/reoxygenation injury. Free Radic Biol Med 2003, 35: 742–751
Pinhasov, A, Mandel, S, Torchinsky, A, Giladi, E, Pittel, Z, Goldsweig, A M, Servoss, S J, Brenneman, D E and Gozes, I.Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res 2003, 144: 83–90
Zaltzman, R, Beni, S M, Giladi, E, Pinhasov, A, Steingart, R A, Romano, J, Shohami, E and Gozes, I.Injections of the neuroprotective peptide NAP to newborn mice attenuate head-injury-related dysfunction in adults. Neuroreport 2003, 14: 481–484
Alcalay, R N, Giladi, E, Pick, C G and Gozes, I.Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze. Neurosci Lett 2004, 361: 128–131
Ashur-Fabian, O, Segal-Ruder, Y, Skutelsky, E, Brenneman, D E, Steingart, R A, Giladi, E and Gozes, I.The neuroprotective peptide NAP inhibits the aggregation of the beta-amyloid peptide. Peptides 2003, 24: 1413–1423