Genetic Signaling in GBM 815 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 surviving 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 816 W.J. Lukiw and F. Culicchia cases. Recent discoveries on the regulation of miRNA-124, miRNA-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 s urgical, 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 Genetic Signaling in GBM 817 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 t he 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 7:191–202 818 W.J. Lukiw and F. Culicchia 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 injection 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 Genetic Signaling in GBM 819 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, B azan 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 18:423–431 820 W.J. Lukiw and F. Culicchia 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 Genetic Signaling in GBM 821 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 Index A 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 823 824 Index 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 with β 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-andγ-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 . 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 823 824 Index Alzheimer. combinatorial therapies involving surgery, radiotherapy, antiangiogenics, MBADs, miRNA antisense strategies, and chemotherapeutics remain as attractive and evolving strategies in the future clinical. systems in vivo remain an imposing biophysical, medical, and clinical research challenge. In the future, combinatorial s urgical, radiotherapeutic, and pharmacological strategies, employing several