ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 3 (2005), No 2, p 67-73

Neuroprotective peptides as drug candidates against Alzheimer's diasease

Jiri Patocka, Jirina Slaninova, Gabriela Kunesova

Address: Jiri Patocka, Department of Toxicology, School of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic

Received 5th November 2004.
Revised 6th December 2004.
Published online 16th March 2005.

Full text article (pdf)

First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is characterized by the presence of neuritic plaques containing the amyloid-beta peptide (Abeta) and an intraneuronal accumulation of tubule-associated protein called tau. Currently available treatment used in AD is based on acetylcholinesterase inhibitors, since in the course of AD there is a substantial loss in cholinergic neurons. Another registered drug used in more severe AD is the NMDA antagonist-memantine. From a drug development point of view, some potential new AD therapeutics include neuroprotective peptides that may act in a variety of different ways, e.g. they help to break the amyloid plaque formation, modulate peptide processing enzymes (secretases) or are able to degrade Abeta toxic peptide. In this review, we present an overview of the new classes of compounds in use against AD.

Alzheimer's disease; neuroprotective peptide; Abeta peptide

Alcalay RN, Giladi E, Pick CG, Gozes I: Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze. Neurosci Lett 361:128-131, 2004.

Bassan M, Zamostiano R, Davidson A et al.: Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem 72:1283-1293, 1999.

Beni-Adani L, Gozes I, Cohen Y et al.: A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injured mice. J Pharmacol Exp Ther 296:57-63, 2000.

Blondel O, Collin C, McCarran B et al.: A glia-derived signal regulating neuronal differentiation. J Neurosci 20:8012-8020, 2000.

Brenneman DE, Spong CY, Hauser JM et al.: Protective peptides that are orally active and mechanistically nonchiral. J Pharm Exp Ther 309:1190-1197, 2004.

Brenneman DE, Gozes I: A femtomolar-acting neuroprotective peptide. J Clin Incest 97:2299-2307, 1996.

Brenneman DE, Hauser J, Neale E et al.: Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides. J Pharmacol Exp Ther 285:619-627, 1998.

Chacon MA, Barria MI, Soto C, Inestrosa NC: Beta-sheet breaker peptide prevents Abeta-induced spatial memory impairments with partial reduction of amyloid deposits. Mol Psychiatry 9:953-961, 2004.

Counts SE, Perez SE, Ginsberg SD, DeLacalle S, Mufson EJ: Galanin in Alzheimer disease. Mol Interv 3:137-156, 2004.

Counts SE, Perez SE, Kahl U: Galanin: neurobiologic mechanisms and therapeutic potential for Alzheimer's disease. CNS Drug Rev 7:445-470, 2001.

Craft S, Asthana S, Newcomer JW et al.: Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56:1135-1140, 1999.

Croom J, Taylor IL: Neuropeptide Y, peptide YY and aluminum in Alzheimer's disease: is there an etiological relationship? J Inorg Biochem 87:51-56, 2001.

Dejda A, Matczak I, Nosak JZ: Postepy. Hig Med Dosw 58:18-26, 2004.

Eldar-Finkelman H: Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med 8:126-132, 2002.

Fisher A, Hanin I: Potential animal models for senile dementia of Alzheimer's type, with emphasis on AF64A-induced cholinotoxicity. Annu Rev Pharmacol Toxicol 26:161-81, 1986.

Glazner GW, Camandola S, Mattson MP: Nuclear factor kappa B mediates the cell survival-promoting action of activity dependent neurotrophic factor peptide-9. J Neurochem 75:101-108, 2000.

Gotz J, Chen F, van Dorpe J, Nitsch RM: Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491-1495, 2001.

Gozes I, Spier AS: Peptides as drug targets to Alzheimer's disease. Drug Develop Res 56:47581, 2002.

Gozes I: Neuroprotective peptide drug delivery and development: potential new therapeutics. Trends Neurosci 24:700-705, 2001.

Gozes I, Brenneman DE: VIP molecular biology and neurobiological function. Mol Neurobiol 3:201-236, 1989.

Gozes I, Giladi E, Pinhasov A, Bardea A, Brenneman DE: Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a watermaze. J Pharmacol Exp Ther 93:1091-1098, 2000.

Gozes I, Divinsky I, Pilzer I et al.: From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division. J Mol Neurosci 20:315-322, 2004.

Gozes I, Fridkin M, Hill JM, Brenneman DE: Pharmaceutical VIP: prospects and problems. Curr Med Chem 6:1019-1034, 1999.

Gozes I, Alcalay R, Giladi E et al.: NAP: a neuroprotective peptide. J Mol Neurosci 19:175-178, 2002.

Gozes I, Steingart RA, Spier AD: NAP mechanisms of neuroprotection. J Mol Neurosci 24:67-72, 2004.

Gressens P, Marret S, Bodenant C, Schwendimann L, 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 13:199-210, 1999.

Guo Q, Sebastian L, Sopher BL et al.: 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 96:4125-4130, 1999.

Guo ZH, Mattson MP: Neurotrophic factors protect cortical synaptic terminals against amyloid and oxidative stress-induced impairment of glucose transport, glutamate transport and mitochondrial function. Cereb Cortex 10:50-57, 2000.

Hashimoto Y, Ito Y, Niikura T et al.: Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun 283:460-468, 2001.

Hirouchi M: Current status and perspectives on the development of therapeutic agents for Alzheimer's disease. (Article in Japanese) Nippon Yakurigaku Zasshi 123:421-427, 2004.

Ioudina M, Uemura E: A three amino acid peptide, Gly-Pro-Arg, protects and rescues cell death induced by amyloid beta-peptide. Exp Neurol 184:923-929, 2004.

Jaarsma D, Veenma-van der Duin L, Korf J: N-acetylaspartate and N-acetylaspartylglutamate levels in Alzheimer's disease post-mortem brain tissue. J Neurol Sci 127:230-233, 1994.

Jhamandas JH, Harris KH, MacTavish D, Jassar BS: Novel excitatory actions of galanin on rat cholinergic basal forebrain neurons: implications for its role in Alzheimer's disease. J Neurophysiol 87:696-704, 2002.

Krejcova G, Patocka J, Slaninova J: Effect of humanin analogues on experimentally induced impairment of spatial memory in rats. J Pept Sci 10:636-639, 2004.

Lin KF, Chang RC, Suen KC, So KF, Hugon J: Modulation of calcium/calmodulin kinase-II provides partial neuroprotection against beta-amyloid peptide toxicity. Eur J Neurosci 19:2047-2055, 2004.

Mamiya T, Ukai M: [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo. Br J Pharmacol 134:1597-1599, 2001.

Mileusnic R, Lancashire CL, Rose SP: The peptide sequence Arg-Glu-Arg, present in the amyloid precursor protein, protects against memory loss caused by A beta and acts as a cognitive enhancer. Eur J Neurosci 19:1933-1938, 2004.

Nieoullon A: Alzheimer's disease: neurobiological advances supporting proposals for new therapeutical approaches. J Appl Biomed 2:123-130, 2004.

Niikura T, Yamada M, Chiba TS et al.: Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. J Neurosci Res 77:54-62, 2004.

Orlando LR, Luthi-Carter R, Standaert DG et al.: N-acetylaspartylglutamate (NAAG) protects against rat striatal quinolinic acid lesions in vivo. Neurosci Lett 236:91-94, 1997.

Passani LA, Vonsattel JP, Carter RE, Coyle JT: N-acetylaspartate and N-acetylaspartylglutamate levels in Alzheimer's disease post-mortem brain tissue. Mol Chem Neuropathol 31:97-118, 1997.

Patocka J, Krejcova G, Borovickova L et al.: Humanin: natural peptide with neuroprotective effect. Homeostasis 42:77-78, 2003.

Patocka J: Memantine and its therapeutic potential in degenerative CNS disorders (Article in Czech). Psychiatrie 6:35-40, 2002.

Patocka J, Slaninova J: Humanin - new peptide in the etiology of Alzheimer's disease (Article in Czech). Ces Slov Psychiat 98:221-222, 2002.

Patocka J, Slaninova J: Neurotoxic peptides related to Alzheimer's disease. Psychiatrie 7(Suppl. 2):99-102, 2003.

Patocka J: Some less known neuromediators. (Article in Czech). Psychiatrie 6(Suppl. 3):36-40, 2002.

Permanne B, Adessi C, Fraga S et al.: Are betasheet breaker peptides dissolving the therapeutic problem of Alzheimer's disease? J Neural Transm 62 (Suppl.):293-301, 2002.

Pompei P, Severini R, Pediconi D et al.: Regulation of preprotachykinin-A gene expression in an animal model of Alzheimer's disease. J Histochem Cytochem 49: 1469-1470, 2001.

Reilly CE: Beta-sheet breaker peptides reverse conformation of pathogenic prion proteins. J Neurol 247:319-320, 2000.

Sheppard PW, Everall I, Anderton BH: Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloidbeta peptide exposure: involvement of Src family protein kinases. J Neurosci 22:10-20, 2002.

Sigalov E, Fridkin M, Brenneman DE, Gozes I: VIP-related protection against iodoacetate toxicity in pheochromocytoma (PC12) cells. A model for ischemic/hypoxic injury. J Mol Neurosci 15:147-154, 2000.

Sisodia SS, Tanzi RE: Special Issue: Alzheimer's disease. J Mol Neurosci 17:99-270, 2001.

Sisodia SS, Annaert W, Kim SH, De Strooper B: Gammasecretase: never more enigmatic. Trends Neurosci 24 (Suppl):S2-S6, 2001.

Slaninova J, Patocka J: Neuroprotective peptides related to Alzheimer's disease (In Czech). Psychiatrie 7(Suppl. 2): 122-123, 2003.

Sokolowska P, Dejda A, Nowak JZ: Neuroprotective role of PACAP, VIP, and PHI in the central nervous system (In Polish). Postepy Hig Med Dosw 58:416-427, 2004.

Steingart RA, Solomon B, Brenneman DE, Fridkin M, Gozes I: VIP and peptides related to activity-dependent neurotrophic factor protect PC12 cells against oxidative stress. J Mol Neurosci 15:137-145, 2000.

Strunecka A, Patocka J: Aluminofluoride complexes in the etiology of Alzheimer's disease. Struct Bonding 104:139-180, 2003.

Strunecka A, Patocka J: Lithium and Alzheimer's disease (In Czech). Psychiatrie 8:13-16, 2004.

Strunecka A, Patocka J, Connet P: Fluorine in medicine. J Appl Biomed 2:141-150, 2004.

Thomas AG, Olkowski JL, Slusher BS: Neuroprotection afforded by NAAG and NAALADase inhibition requires glial cells and metabotropic glutamate receptor activation. Eur J Pharmacol 426:35-38, 2001.

Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim MB: Neuroprotection via prosurvival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 18:1471-1473, 2004.

White DM, Walker S, Brenneman DE, Gozes I: CREB contributes to the increased neurite outgrowth of sensory neurons induced by vasoactive intestinal polypeptide and activitydependent neurotrophic factor. Brain Res 868:31-38, 2000.

Williamson R, Scales T, Clark BR et al.: Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol 172:7078-7085, 2004.

Xie J, Guo Q: AATF protects neural cells against oxidative damage induced by amyloid betapeptide. Neurobiol Dis 16:150-157, 2004.

Zamostiano R, Pinhasov A, Gelber E et al.: Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem 276:708-714, 2001.

Zamostiano R, Pinhasov A, Bassan M et al.: A femtomolar-acting neuroprotective peptide induces intracellular increases in heat shock protein 60: a potential neuroprotective mechanism. Neurosci Lett 264:9-12, 1999.

Zhu X, Wang Y, Ogawa O et al.: Neuroprotective properties of Bcl-w in Alzheimer disease. J Neurochem 89:1233-1240, 2004.

Yang M-H, Yang Y-H, Lu C-Y, Jong S-B, Chen L-J, Lin Y-F, Wu S-J, Chu P-Y, Chung T-W, Tyan Y-C. Activity-dependent neuroprotector homeobox protein: A candidate protein identified in serum as diagnostic biomarker for Alzheimer's disease. J Proteom. 75: 3617-3629, 2012.

Lin Y-F, Yang M-H, Yang Y-H, Chen W-C, Lu C-Y, Peng C-F, Jong S-B, Chen L-J, Wu S-J, Chu P-Y, Chung T-W, Tyan Y-C. Activity-dependent neuroprotector homeobox protein level in Alzheimer's disease in Taiwanese. Genom Med Biomark Health Sci. 4: 48-50, 2012.

Robertson ChR, Pruess TH, Grussendorf E, White HS, Bulaj G. Generating orally active galanin analogues with analgesic activities. Chemmedchem. 7: 903-909, 2012.

Kristofikova Z, Patocka J, Ripova D. Stereospecific interactions of amyloid beta peptides. [Stereospecificke interakce peptidu amyloidu beta]. Psychiatrie. 14: 18-21, 2010.

Alonso AD, Corbo CP. Novel therapeutics based on tau/microtubule dynamics: WO2008084483. Expert Opin Therapeutic Patents. 19: 1335-1338, 2009.

Antonyan AA, Sharoyan SG, Harutyunyan AA, Mardanyan SS. Influence of aluminum toxicosis on the activity of adenosine deaminase and dipeptidyl peptidases II and IV. Neurochem J. 3: 118-121, 2009.

Stevenson CL. Advances in Peptide Pharmaceuticals. Curr Pharm Biotechnol. 10: 122-137, 2009.

Kunesova G, Hlavacek J, Patocka J, Kunesova G, Evangelou A, Zikos C, Benaki D, Paravatou-Petsotas M, Pelecanou M, Livaniou E, Slaninova J. The multiple T-maze in vivo testing of the neuroprotective effect of humanin analogues. Pept. 29: 1982-1987, 2008.

Havel J, Li R, Macka M. CE study of neuroprotective humanin peptide and its derivatives: Interactions with phosphate, sulphate, alkylsulphonates and sulphated-beta-CD. Electrophoresis. 29: 665-671, 2008.

Thompson SM, Sinha S, Topp EM, Camarda KV. A molecular design approach to peptide drug stabilization. Conference Information: Annual Meeting of the American-Institute-for-Chemical-Engineers (AIChE), Oct 30-Nov 04, 2005 Cincinnati, OH. Mol Simul. 32: 291-295, 2006.