Neurochemical Mechanisms in Disease P84 ppsx

Although individual genetic signaling patterns are variable, increases in the expression of glioma and GBM markers, such as beta-amyloid precursor protein, caspase-3, pentraxin-2, and va

outside of the CNS (Zhang and Lippard, 2003 ) In fact, despite the synthesis of thousands of compounds over the last decade only very few novel neurotoxic MBADs have successfully reached the clinical development stage in brain cancer chemotherapy (Zhang and Lippard, 2003 ; Heffeter et al., 2008 ).

Anti-miRNA therapeutic strategies remain attractive in that single miRNAs may interact with the expression of a relatively large number of dysregulated pathogenic genes in neurological disease processes (Corsten et al., 2007 ; Lukiw

et al., 2009 ) For example miRNA-21 levels have been reported to be elevated in glioma and their knock-down is associated with increased apoptotic activity The use

of anti-miRNA-21 oligonucleotides in vitro shows that suppression of miRNA-21 leads to a synergistic increase in caspase-3 activity and decreased cell viability (Corsten et al., 2007 ) Similar effects on the use of miRNA-based therapies on the stem-cell-like characteristics of glioma have been suggested to have considerable therapeutic potential (Godlewski et al., 2008 ; Hide et al., 2008 ) The development of advanced combinatorial therapies involving surgery, radiotherapy, antiangiogenics, MBADs, miRNA antisense strategies, and chemotherapeutics remain as attractive and evolving strategies in the future clinical management of glioma and GBM.

9 Summary

Glioma and glioblastoma multiforme constitute highly complex, progressive, and insidious neoplastic disorders of the human CNS Those treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 12 months, with fewer than 25% of patients sur-viving up to two years and fewer than 10% of patients sursur-viving up to five years Whether the prognosis of patients with secondary glioblastoma is better than, or similar to, those patients with primary glioblastoma remains controversial Glioma and GBM each exhibit significantly heterogeneous gene expression profiles, and spontaneous, dysregulated, and highly proliferative invasive cell growth Although individual genetic signaling patterns are variable, increases in the expression of glioma and GBM markers, such as beta-amyloid precursor protein, caspase-3, pentraxin-2, and vascular endothelial growth factor, indicate upregulated expres-sion of cell–cell contact, cell cycle, vascular proliferation, and apoptotic–necrotic markers at the level of gene expression in virtually all brain tumors examined The heterogeneous genotypic and phenotypic nature of human brain neoplasms further confounds their molecular and genetic signature as well as pharmacological and therapeutic treatment strategies.

Surgical resection followed by aggressive radiotherapy and chemotherapy using genomic methylating agents, such as temozolomide (TMZ), and tailored to each individual case, currently represents the best treatment options available Surgical and multimodal radiotherapeutic approaches combined with chemotherapeutic agents, each with independent and sometimes synergistic mechanisms of action, are currently providing the greatest clinical benefit with improved quality of life in many

cases Recent discoveries on the regulation of 124, 125b,

miRNA-137 and miRNA-221 expression are uncovering another layer of genetic control

in neoplastic brain cells, and should provide yet another therapeutic approach, and treatment opportunity, for advanced clinical intervention The design and applica-tion of novel micro-RNA-based therapeutic strategies are highly attractive because

a single miRNA may be able to quench the expression of entire families of interre-lated neoplastic or oncogenic genes Several of these novel approaches have been proven to be effective in vitro, however, miRNA and drug delivery systems in vivo remain an imposing biophysical, medical, and clinical research challenge In the future, combinatorial surgical, radiotherapeutic, and pharmacological strategies, employing several genomic structure and function modifiers simultaneously, appear

to hold the most promise for advancing the clinical management of brain cancer and improvement in the prognosis for both the glioma and GBM patient.

Acknowledgments The work in this manuscript was supported by a Translational Research

Initiative (TRI) Grant entitled “Gene expression patterns in glioblastoma multiforme (GBM)” by

the Louisiana State University Board of Regents

References

Amaral PP, Dinger ME, Mercer TR, Mattick JS (2008) The eukaryotic genome as an RNA machine Science 319:1787–1789

Anderson JC, McFarland BC, Gladson CL (2008) New molecular targets in angiogenic vessels of glioblastoma tumours Expert Rev Mol Med 10:e23

Bates KA, Fonte J, Robertson TA, Martins RN, Harvey AR (2002) Chronic gliosis triggers Alzheimer’s disease-like processing of amyloid precursor protein Neuroscience 113:785–796 Bauer N, Fonseca AV, Florek M, Freund D, Jászai J, Bornhäuser M, Fargeas CA, Corbeil D (2008) New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133) Cells Tissues Organs 188:127–138

Belda-Iniesta C, de Castro Carpeño J, Casado Sáenz E, Cejas Guerrero P, Perona R, González Barón M (2006) Molecular biology of malignant gliomas Clin Transl Oncol 8:635–641 Boudreau CR, Yang I, Liau LM (2005) Gliomas: advances in molecular analysis and characteriza-tion Surg Neurol 64:286–294

Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas Lancet Oncol 9:453–461 Bruce JN, Criscuolo GR, Merrill MJ, Moquin RR, Blacklock JB, Oldfield EH (1987) Vascular per-meability induced by protein product of malignant brain tumors: inhibition by dexamethasone

J Neurosurg 67:880–884

Buie LW, Valgus J (2008) Bevacizumab: a treatment option for recurrent glioblastoma multiforme Ann Pharmacother 42:1486–1490

Caltagarone J, Jing Z, Bowser R (2007) Focal adhesions regulate amyloid signaling and cell death

in Alzheimer’s disease Biochim Biophys Acta 1772:438–445

Cao X, Pfaff SL, Gage FH (2007) A functional study of miR-124 in the developing neural tube Genes Dev 21:531–536

Cao X, Yeo G, Muotri AR, Kuwabara T, Gage FH (2006) Noncoding RNAs in the mammalian central nervous system Annu Rev Neurosci 29:77–103

Carlson MR, Pope WB, Horvath S, Braunstein JG, Nghiemphu P, Tso CL, Mellinghoff I, Lai A, Liau LM, Mischel PS, Dong J, Nelson SF, Cloughesy TF (2007) Relationship between sur-vival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2 Clin Cancer Res 13:2592–2598

Chamberlain MC (2008) Antiangiogenic blockage: a new treatment for glioblastoma Expert Opin Biol Ther 8:1449–1453

Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma – animal models and therapeutic challenges Brain Pathol 19:112–120

Cho WC (2007) OncomiRs: the discovery and progress of microRNAs in cancers Mol Cancer 6:60

Ciafrè SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, Negrini M, Maira G, Croce

CM, Farace MG (2005) Extensive modulation of a set of microRNAs in primary glioblastoma Biochem Biophys Res Commun 334:1351–1358

Colangelo V, Schurr J, Ball MJ, Palacios Pelaez R, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12,633 genes in Alzheimer hippocampal CA1 J Neurosci Res 70:462–473 Conaco C, Otto S, Han JJ, Mandel G (2006) Reciprocal actions of REST and a microRNA promote neuronal identity Proc Natl Acad Sci U S A 103:2422–2427

Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K (2007)

MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas Cancer Res 67:8994–9000

Culicchia F, Cui JG, Li YY, Lukiw WJ (2008) Upregulation of beta-amyloid precursor protein (βAPP) expression in glioblastoma multiforme NeuroReport 19:981–985

Dogini DB, Ribeiro PA, Rocha C, Pereira TC, Lopes-Cendes I (2008) MicroRNA expression profile in murine central nervous system development J Mol Neurosci 35:331–337

Emsley J, White HE, O’Hara BP, Oliva G, Srinivasan N, Tickle IJ, Blundell TL, Pepys MB, Wood

SP (1994) Structure of pentameric human serum amyloid P component Nature 367:338–345 Farrell CJ, Plotkin SR (2007) Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes Neurol Clin 25:925–946

Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P (2007) Molecular profiling identi-fies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors J Clin Oncol 25:1196–1208

Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, Felli N, Mattia G, Petrini M, Colombo MP, Peschle C, Carè A (2008) The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms Cancer Res 68:2745–2754

Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL (2007) Epidemiology of brain tumors Neurol Clin 25:867–890

Fuller GN, Hess KR, Rhee CH, Yung WK, Sawaya RA, Bruner JM, Zhang W (2002) Molecular classification of human diffuse gliomas by multidimensional scaling analysis of gene expres-sion profiles parallels morphology-based classification, correlates with survival, and reveals clinically-relevant novel glioma subsets Brain Pathol 12:108–116

Fuso A, Cavallaro RA, Zampelli A, D’Anselmi F, Piscopo P, Confaloni A, Scarpa S (2007) gamma-secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells J Alzheimers Dis 11:275–290

Gerrow K, El-Husseini A (2007) Receptors look outward: revealing signals that bring excitation to synapses Sci STKE 408:56

Giles FJ (2001) The vascular endothelial growth factor (VEGF) signaling pathway: a therapeutic target in patients with hematologic malignancies Oncologist 6:32–39

Gillies JK, Lorimer IA (2007) Regulation of p27Kip1 by miRNA 221/222 in glioblastoma Cell Cycle 6:2005–2009

Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S (2008) Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibitsglioma proliferation and self-renewal Cancer Res 68: 9125–9130

Goodman AR, Cardozo T, Abagyan R, Altmeyer A, Wisniewski HG, Vilcek J (1996) Long pen-traxins: an emerging group of proteins with diverse functions Cytokine Growth Factor Rev 7:191–202

Grothey A, Ellis LM (2008) Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies Cancer J 14:170–177

Grothey E, Gibson T, Sartor O, Bukowski R (2008) Highlights from: the 2008 meeting of the American Society of Clinical Oncology, May 30–June 3, 2008, Chicago, IL Clin Genitourin Canc 6:65–72

Gurdon JB, Melton DA (2008) Nuclear reprogramming in cells Science 322:1811–1815 Hasan J, Jayson GC (2001) VEGF antagonists Expert Opin Biol Ther 1:703–718

Heffeter P, Jungwirth U, Jakupec M, Hartinger C, Galanski M, Elbling L, Micksche M, Keppler

B, Berger W (2008) Resistance against novel anticancer metalcompounds: differences and similarities Drug Resist Updat 11:1–16

Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N (2007) Microglial activa-tion is required for Abeta clearance after intracranial injecactiva-tion of lipopolysaccharide in APP transgenic mice J Neuroimmune Pharmacol 2:222–231

Hide T, Takezaki T, Nakamura H, Kuratsu J, Kondo T (2008) Brain tumor stem cells as research and treatment targets Brain Tumor Pathol 25:67–72

Hill JM, Zhao Y, Clement C, Neumann DM, Lukiw WJ (2009) HSV-1 infection of human brain cells induces miRNA-146a and Alzheimer-type inflammatory signaling Neuroreport 20:1500– 1505

Hobert O (2008) Gene regulation by transcription factors and microRNAs Science 319:1785–1786 Hsu YC, Perin MS (1995) Human neuronal pentraxin II (NPTX2): conservation, genomic structure, and chromosomal localization Genomics 28:220–227

Huang PH, Cavenee WK, Furnari FB, White FM (2007) Uncovering therapeutic targets for glioblastoma: a systems biology approach Cell Cycle 6:2750–2754

Hyun Hwang J, Smith CA, Salhia B, Rutka JT (2008) The role of fascin in the migration and invasiveness of malignant glioma cells Neoplasia 10:149–159

Idbaih A, Omuro A, Ducray F, Hoang-Xuan K (2007) Molecular genetic markers as predictors of response to chemotherapy in gliomas Curr Opin Oncol 19:606–611

Johansson Swartling F (2008) Identifying candidate genes involved in brain tumor formation Ups

J Med Sci 113:1–38

Juric D, Bredel C, Sikic BI, Bredel M (2007) Integrated high-resolution genome-wide analysis of gene dosage and expression in human brain tumors Methods Mol Biol 377:187–202 Kavsan VM, Dmitrenko VV, Shostak KO, Bukreieva TV, Vitak NY, Simirenko OE, Malisheva

TA, Shamayev MI, Rozumenko VD, Zozulya YA (2007) Comparison of microarray and sage techniques in gene expression analysis of human glioblastoma Tsitol Genet 41: 36–55

Kavsan V, Shostak K, Dmitrenko V, Zozulya Y, Rozumenko V, Demotes-Mainard J (2005) Characterization of genes with increased expression in human glioblastomas Tsitol Genet 39:37–49

Koul D (2008) PTEN signaling pathways in glioblastoma Cancer Biol Ther 7:1321–1325 Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis Nat Genet 39:673–677

Lahiri DK, Farlow MR, Nurnberger JI Jr, Greig NH (1997) Effects of cholinesterase inhibitors

on the secretion of beta-amyloid precursor protein in cell cultures Ann N Y Acad Sci 826: 416–421

Lakka SS, Rao JS (2008) Antiangiogenic therapy in brain tumors Expert Rev Neurother 8: 1457–1473

Larrivee B, Karsan A (2000) Signaling pathways induced by vascular endothelial growth factor (review) Int J Mol Med 5:447–456

Lefranc F, Facchini V, Kiss R (2007) Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas Oncologist 12: 1395–1403

le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, Anile C, Maira G, Mercatelli

N, Ciafrè SA, Farace MG, Agami R (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation EMBO J 26:3699–3708

Levicar N, Dewey RA, Daley E, Bates TE, Davies D, Kos J, Pilkington GJ, Lah TT (2003) Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis Cancer Gene Ther 10:141–151

Levicar N, Strojnik T, Kos J, Dewey RA, Pilkington GJ, Lah TT (2002) Lysosomal enzymes, cathepsins in brain tumour invasion J Neurooncol 58:21–32

Li F, Ackermann EJ, Bennett CF (1999) Pleiotropic cell-division defects and apoptosis induced by interference with survivin function Nat Cell Biol 1:461–466

Lopes MBS, VandenBerg SR, Scheithauer BW (1993) The World Health Organization classi-fication of nervous system tumors in experimental neuro-oncology In: AJ Levine and HH Schmidek, eds Molecular Genetics of Nervous System Tumors Wiley-Liss, New York, NY,

pp 1–36

Louis DN (2006) Molecular pathology of malignant gliomas Annu Rev Pathol 1:97–117 Lukiw WJ (2004) Gene expression profiling in fetal, aged, and Alzheimer hippocampus: a continuum of stress-related signaling Neurochem Res 29:1287–1297

Lukiw WJ (2007) Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus NeuroReport 18:297–300

Lukiw WJ (2009) Docosahexaenoic acid and amyloid-beta peptide signaling in Alzheimer’s disease World Rev Nutr Diet 99:55–70

Lukiw WJ, Bazan NG (2006) Survival signaling in Alzheimer’s disease Biochem Soc Trans 34:1277–1282

Lukiw WJ, Bazan NG (2008) Docosahexaenoic acid and the aging brain J Nutr 138:2510–2514 Lukiw WJ, Carver LA, LeBlanc HJ, Bazan NG (2000) Analysis of 1184 gene transcript levels in

AD CA1 hippocampus: synaptic signaling and transcription factor deficits and upregulation of pro-inflammatory pathways Alzheimers Rep 3:161–167

Lukiw WJ, Cui JG, Li YY, Culicchia F (2009) Up-regulation of micro-RNA-221 (miRNA-221; chr Xp11.3) and caspase-3 accompanies down-regulation of the survivin-1 homolog BIRC1 (NAIP) in glioblastoma multiforme(GBM) J Neurooncol 91:27–32

Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K (2005) A role for docosa-hexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease J Clin Invest 115:2774–2783

Lukiw WJ, Cui JG, Zhao Y, Cui JG (2008) An NF-kB-sensitive microRNA-146a-mediated inflammatory circuit in Alzheimer’s disease and in stressed human brain cells, J Biol Chem 283:31315–31322

Lukiw WJ, Ottlecz A, Lambrou G, Grueninger M, Finley J, Thompson HW, Bazan NG (2003) Coordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expres-sion in retinal cells by hypoxia Invest Ophthalmol Vis Sci 44:4163–4170

Lukiw WJ, Pogue AI (2007) Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells J Inorg Biochem 101:1265–1269

MacDonald TJ, Pollack IF, Okada H, Bhattacharya S, Lyons-Weiler J (2007) Progression-associated genes in astrocytoma identified by novel microarray gene expression data reanalysis Methods Mol Biol 377:203–222

Makeyev EV, Maniatis T (2008) Multilevel regulation of gene expression by microRNAs Science 319:1789–1790

Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing Mol Cell 27:435–448

Mattick JS, Amaral PP, Dinger ME, Mercer TR, Mehler MF (2009) RNA regulation of epigenetic processes Bioessays 31:51–59

Mattick JS, Makunin IV (2005) Small regulatory RNAs in mammals Hum Mol Genet 14:121–132 Medina R, Zaidi SK, Liu CG, Stein JL, van Wijnen AJ, Croce CM, Stein GS (2008) MicroRNAs 221 and 222 bypass quiescence and compromise cell survival Cancer Res 68: 2773–2780

Mehlhorn G, Hollborn M, Schliebs R (2000) Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice Int J Dev Neurosci 18:423–431

Mellai M, Caldera V, Patrucco A, Annovazzi L, Schiffer D (2008) Survivin expression in glioblastomas correlates with proliferation, but not with apoptosis Anticancer Res 28:109–118 Mourelatos Z (2008) MicroRNAs: biology and roles in neurodegeneration and brain tumours Introduction and historical background Brain Pathol 18:110–112

Nelson JS (2002) Alzheimer pathology in elderly patients with glioblastoma multiforme Arch Pathol Lab Med 126:1515–1517

Nicholas MK, Lukas RV, Jafri NF, Faoro L, Salgia R (2006) Epidermal growth factor receptor – mediated signal transduction in thedevelopment and therapy of gliomas Clin Cancer Res 12:7261–7270

Nicoloso MS, Calin GA (2008) Micro RNA involvement in brain tumors: from bench to bedside Brain Pathol 18:122–129

Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas Lancet Neurol 7:1152–1160

Ohgaki H (2009) Epidemiology of brain tumors Methods Mol Biol 472:323–342

Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas J Neuropathol Exp Neurol 64:479–489 Papagiannakopoulos T, Kosik KS (2008) MicroRNAs: regulators of oncogenesis and stemness BMC Med 6:15

Paris D, Quadros A, Patel N, DelleDonne A, Humphrey J, Mullan M (2005) Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors Eur J Pharmacol 514:1–15

Pluta R (2002) Astroglial expression of the beta-amyloid in ischemia-reperfusion brain injury Ann

N Y Acad Sci 977:102–108

Pogue AI, Cui JG, Li YY, Zhao Y, Culicchia F, Lukiw WJ (2010) Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation Neurosci Lett 476(1):18–22

Pogue AI, Lukiw WJ (2004) Angiogenic signaling in Alzheimer’s disease Neuroreport 15:1507–1510

Pope WB, Chen JH, Dong J, Carlson MR, Perlina A, Cloughesy TF, Liau LM, Mischel

PS, Nghiemphu P, Lai A, Nelson SF (2008) Relationship between gene expression and enhancement in glioblastoma multiforme: exploratory DNA microarray analysis Radiology 249:268–277

Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L (2007) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology EMBO Rep 7: 940–946

Ray SK, Patel SJ, Welsh CT, Wilford GG, Hogan EL, Banik NL (2002) Molecular evidence of apoptotic death in malignant brain tumors includingglioblastoma multiforme: upregulation of calpain and caspase-3 J Neurosci Res 69:197–206

Reardon DA, Wen PY, Desjardins A, Batchelor TT, Vredenburgh JJ (2008) Glioblastoma multi-forme: an emerging paradigm of anti-VEGF therapy Expert Opin Biol Ther 8:541–553 Rosell R, de Las Peñas R, Balaña C, Santarpia M, Salazar F, de Aguirre I, Reguart N, Villa S, Wei J, Ramirez JL, Molina MA, Ramon y, Cajal S, Jablons D, Taron M (2008) Translational research in GBM: molecular criteria for patient selection Future Oncol 4:219–228

Rueger MA, Winkeler A, Thomas AV, Kracht LW, Jacobs AH (2008) Molecular imaging-guided gene therapy of gliomas Handb Exp Pharmacol 185:341–359

Sathornsumetee S, Reardon DA (2009) Targeting multiple kinases in glioblastoma multiforme Expert Opin Investig Drugs 18:277–292

Sathornsumetee S, Rich JN (2008) Designer therapies for glioblastoma multiforme Ann N Y Acad Sci 1142:108–132

Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells andinduce differentiation of brain tumor stem cells BMC Med 6:14

Sin AH, Gonzalez-Toledo E, Fowler M, Minagar A, Nanda A (2008) Amyloidoma presenting as a butterfly glioma on positron emission tomography scan and magnetic resonance-spectroscopy:

a case report and review of the literature J La State Med Soc 160:44–50

Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors Oncogene 23:7267–7273

Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification

of a cancer stem cell in human brain tumors Cancer Res 63:5821–5828

Stegh AH, Kesari S, Mahoney JE, Jenq HT, Forloney KL, Protopopov A, Louis DN, Chin L, DePinho RA (2008) Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinctmechanisms in glioblastoma Proc Natl Acad Sci U S A 105:10703–10708

Sutcliffe JG (2001) Open-system approaches to gene expression in the CNS J Neurosci 21: 8306–8309

Takuma K, Baba A, Matsuda T (2004) Astrocyte apoptosis: implications for neuroprotection Prog Neurobiol 72:111–127

Tatter SB 2005 The new WHO classification of tumors affecting the human central nervous system.http://neurosurgery.mgh.harvard.edu/newwhobt.htm#Mutations

Tentori L, Graziani G (2009) Recent approaches to improve the antitumor efficacy of temozolo-mide Curr Med Chem 16:245–257

Tschape JA, Hartmann T (2008) Therapeutic perspectives in Alzheimer’s disease Recent Pat CNS Drug Discov 1:119–127

Tso CL, Freije WA, Day A, Chen Z, Merriman B, Perlina A (2006) Distinct transcription profiles

of primary and secondary glioblastoma subgroups Cancer Res 66:159–167

van den Bent MJ, Kros JM (2007) Predictive and prognostic markers in neuro-oncology J Neuropathol Exp Neurol 66:1074–1081

Venezia V, Nizzari M, Carlo P, Corsaro A, Florio T, Russo C (2007) Amyloid precursor protein and presenilin involvement in cell signaling Neurodegener Dis 4:101–111

Voelzke WR, Petty WJ, Lesser GJ (2008) Targeting the epidermal growth factor receptor in high-grade astrocytomas Curr Treat Options Oncol 9:23–31

Williams AE, Perry MM, Moschos SA, Larner-Svensson HM, Lindsay MA (2008) Role of miRNA-146a in the regulation of the innate immune response and cancer Biochem Soc Trans 36:1211–1215

Wong ET, Brem S (2008) Antiangiogenesis treatment for glioblastoma multiforme: challenges and opportunities J Natl Compr Canc Netw 6:515–522

Xie Z, Chin LS (2008) Molecular and cell biology of brain tumor stem cells: lessons from neuralprogenitor/stem cells Neurosurg Focus 24:E25

Xie Q, Thompson R, Hardy K, DeCamp L, Berghuis B, Sigler R, Knudsen B, Cottingham S, Zhao

P, Dykema K, Cao B, Resau J, Hay R, Vande Woude GF (2008) A highly invasive human glioblastoma pre-clinical model for testing therapeutics J Transl Med 6:77–97

Yadirgi G, Marino S (2009) Adult neural stem cells and their role in brain pathology J Pathol 217:242–253

Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ (2007) A critical function for beta-amyloid precursor protein in neuronal migration J Neurosci 27:14459–14469

Zeng Y (2009) Regulation of the mammalian nervous system by microRNAs Mol Pharmacol 75:259–264

Zhang CX, Lippard SJ (2003) New metal complexes as potential therapeutics Curr Opin Chem Biol 7:481–489

Zhang B, Pan X, Cobb GP, Anderson TA (2007) microRNAs as oncogenes and tumor suppressors Dev Biol 302:1–12

Zhao Y, Cui JG, Lukiw WJ (2006) Natural secretory products of human neural and microvessel endothelial cells: Implications in pathogenic “spreading” of neurodegenerative disease Mol Neurobiol 34:181–192

Aberrant caspase activity,342–343

Acetylcholine (ACh),389,422

class I,422–425

Acetylcholinesterase,266–267

inhibitors,618

Acetyl-L-carnitine (ALC) treatment

for AD,620

ACh, see Acetylcholine (ACh)

Acute heat pain

latency,484

test,475,483

N-Acylphosphatidyl-ethanolamine

(NAPE),471

Addiction

alcoholism,181–182

psychostimulant,180–181

Adenosine,268–269,438–439,570

molecular role of,268

Adherent junctions

PECAM-1,128,131

VE-cadherin,128,131

Adhesion,567

ADNFLE, see Autosomal dominant nocturnal

frontal lobe epilepsy (ADNFLE)

Adrenomyeloneuropathy (AMN),564

Aging,259

advanced,270

conversion to MCI,272–273

default network,271

disconnection hypothesis,270–271

MCI/AD diagnosis,271

Agmatine (AGM),432

Alcohol

pellagra,115

thiamine deficiency,110

Wernicke’s encephalopathy (WE),110

Alcoholism

role of DAT promoter hypermethylation in,

181–182

Alexander disease (AxD),565

Alpha-synuclein,281

aggregation,661

Alzheimer disease (AD),245,411,588

amyloid-β peptide,612–614

Aβ-injected rodent,64–65

Aβ1-42 oligomer,613

AβPP,611

APOE

ε allele of gene,611

gene,701

gene function and expression,710–712

gene location and structure,710

genetic variation,712

inheritance and clinical features,710

structure and single nucleotide polymorphisms,711

APP structure and mutations,703

autosomal dominant, genes associated with gene function and expression,703–704

gene location and structure,703

genetic variation,704–705

inheritance and clinical features,

702–703

behavioral and cognitive decline,610–611

case report,269–270

clinical diagnosis

DSM-IV, 699

MMSE and CADASIL,699

clinical features,651–652

clinical symptoms early-onset AD (EOAD),698

and late-onset AD (LOAD),698

treatment of,699

defined,610

diagnosis,273–274

diet in,274

J.P Blass (ed.), Neurochemical Mechanisms in Disease,

Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3,

C

Springer Science+Business Media, LLC 2011

823

Alzheimer disease (AD) (cont.)

early-onset familial AD (EOFAD)

genetics of,701

EOFAD,701

genetic influence in,611

human

diagnosis,52–53

familial AD (FAD),52

neuropathological hallmarks,52

sporadically (SAD),52

imaging,274–276

integrated approach,276

invertebrate models

advantages,62

APP and APPL,62

C elegans, 62–63

sea lamprey,62

model of disconnected neuron,280

nAChRs

altered expression,763–764

withβ amyloid, interaction of,764–765

neurochemistry and neurobiology

cell cycle re-entry hypothesis,656–657

genomic instability model,657

interaction of ApoE and Tau,656

neurobiology of NFT,654–656

tau hyperphosphorylation,652–654

neuropathological diagnosis

amyloid plaques,699

APP cleavage,700

Congo red-positive fibrillar,699

EOAD,701

neurons,701

neuropathology,652

oxidative DNA damage,611

oxidative stress associated with,610

and Parkinson’s disease genes,702

pharmacological treatments for

antiglutamatergic treatment,618

antioxidants,620

antioxidant therapies,618

Aβ channel blockers,618

Aβ immunotherapy,618

cholesterol-lowering drugs,618

cholinesterase inhibitors,618

epidemiological data,619

hormonal replacement therapy,618

nonsteroidal anti-inflammatory

drugs,618

Phase II trial,619

rivastigmine and galactine,618

β- and γ-secretase inhibitors,618

tacrine and donepezil,618

presenilin 1,705

gene function and expression,706–707

gene location and structure,706

genetic variation,707–708

inheritance and clinical features,

705–706

structure and mutations,707

presenilin 2 gene function and expression,708–709

gene location and structure,708

genetic variation,709

inheritance and clinical features,708

structure and mutations,709

presenilin 1 gene (PSEN1),701

mutations,269–270

prevalence and incidence early-onset AD (EOAD),698

and late-onset AD (LOAD),698

primate model, approaches lesioning,63–64

pharmacological,64

spontaneous,63

risk factors for,673

diabetes and hyperlipidemia,674

elevated plasma homocysteine,674

head injury,674

hypertension and heart disease,674

low educational attainment,674

low linguistic ability early in life,674

obesity,674

smoking,674

rodent models pharmacological,53

transgenic mouse,53–60

transgenic rat,60–62

synaptic dysfunction,279

imaging data,281

neuropathological studies,279

role of tau,281

tau protein,614

abnormal phosphorylation and,615

gene mutations,611

isoforms in,657–658

American Type Tissue Collection (ATCC),812

2-Aminoethanesulfonic acid,436

AMP-activated protein kinase (AMPK),794

Amyloid-β peptide (Aβ),612

in oxidative stress,588–590

and tau interaction,278–279

Amyloid precursor protein (APP),270,273,

276–277,376,589,597–598

amyloidogenic mouse models,277

mutations,673