| 研究生: |
潘佳昕 Pan, Chia-Hsin |
|---|---|
| 論文名稱: |
探討血漿去氧核醣核酸於阿茲海默氏症之應用 The role of plasma circulating nucleic acids in Alzheimer’s disease |
| 指導教授: |
蔡坤哲
Tsai, Kuen-Jer |
| 共同指導教授: |
楊尚訓
Yang, Shang-Hsun |
| 學位類別: |
碩士 Master |
| 系所名稱: |
醫學院 - 生理學研究所 Department of Physiology |
| 論文出版年: | 2013 |
| 畢業學年度: | 101 |
| 語文別: | 英文 |
| 論文頁數: | 80 |
| 中文關鍵詞: | 阿茲海默氏症 、游離態核酸 、生物標的 |
| 外文關鍵詞: | Alzheimer’s disease, circulating nucleic acid, biomarker |
| 相關次數: | 點閱:58 下載:2 |
| 分享至: |
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阿茲海默症是一種漸進式神經退化性疾病,其病理特徵主要於腦中會出現β類澱粉斑塊 (β-amyloid plaques)的沉積、細胞內神經纖維糾結、慢性神經炎以及神經細胞的損傷,進而造成認知功能毀滅性的傷害。目前阿茲海默症之臨床診斷主要藉由神經心理測驗評量患者的認知功能,並透過昂貴的腦部影像技術來觀察腦部的病理特徵, 然而需於患者腦部已有明顯的病理變化與神經細胞損傷後才能透過現行的診斷工具進一步確認,因此,發展能應用於阿茲海默氏症早期診斷的生物標的是日前相當感興趣的探究議題。近十年來發現,癌症、糖尿病、中風、嚴重外傷以及全身紅斑性狼瘡患者的血漿中皆能偵測到高濃度的游離態核酸的表現,目前認為患者血漿中高濃度的游離態核酸表現可能是由於疾病誘發大量細胞凋亡而導致游離態核酸釋放至週邊血液中所造成的現象。阿茲海默氏症是由於神經細胞遭受β類澱粉斑塊毒性攻擊,進而誘發神經細胞凋亡,因此本篇研究將探討血漿中的游離態核酸是否能作為阿茲海默氏症臨床診斷之生物標的。
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles, low-level chronic neuroinflammation and neuronal injury, resulting in a devastating loss of cognitive function. Current clinical diagnosis of AD requires neuropsychological testing and costly brain imaging techniques, when significant brain pathology and neuronal injury has already transpired. There is growing interest for identification of new targets for early detectable biomarker in AD. In the past 10 years, several other reports followed related to the detection of high fractional concentrations of circulating nucleic acids (CNAs) in the plasma of patients with cancers, diabetes, stroke, trauma and rheumatoid arthritis. It is likely that cell apoptosis is the major mechanism by which nucleic acids are released from cell into the circulation. This study hypothesizes that since CNAs substantially increase after neuron degenerated, the level of CNAs can be used as a predictive marker of AD progression. Therefore, in this thesis, we would like o examine whether the CNAs also could be a potential diagnostic marker in AD.
1. Selkoe DJ (2001) Alzheimer's disease: genes, proteins, and therapy. Physiological reviews 81(2):741-766.
2. Hardy J & Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297(5580):353-356.
3. Plassman BL, et al. (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29(1-2):125-132.
4. Lu PH, et al. (2009) Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology 72(24):2115-2121.
5. BrainGalimberti D & Scarpini E (2011) Disease-modifying treatments for Alzheimer's disease. Therapeutic advances in neurological disorders 4(4):203-216.
6. Jack CR, Jr., et al. (2009) Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain : a journal of neurology 132(Pt 5):1355-1365.
7. Petersen RC, et al. (2001) Current concepts in mild cognitive impairment. Archives of neurology 58(12):1985-1992.
8. Angel Cedazo-Minguez & Winblada. B (2010) Biomarkers for Alzheimer’s disease and other forms of dementia: Clinical needs, limitations and future aspects Experimental Gerontology 45(1):5-14
9. Blennow K, Hampel H, Weiner M, & Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nature reviews. Neurology 6(3):131-144.
10. Ann NeurolArcher HA, et al. (2006) Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study. Annals of neurology 60(1):145-147.
11. Fagan AM, et al. (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Annals of neurology 59(3):512-519.
12. Forsberg A, et al. (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiology of aging 29(10):1456-1465.
13. Buerger K, et al. (2006) CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain : a journal of neurology 129(Pt 11):3035-3041.
14. Hampel H, et al. (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Archives of neurology 62(5):770-773.
15. Hesse C, et al. (2001) Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neuroscience letters 297(3):187-190.
16. Ost M, et al. (2006) Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 67(9):1600-1604.
17. Blennow K (2004) Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 1(2):213-225.
18. Blennow K & Hampel H (2003) CSF markers for incipient Alzheimer's disease. Lancet Neurol 2(10):605-613.
19. Hansson O, et al. (2006) Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5(3):228-234.
20. Irizarry MC (2004) Biomarkers of Alzheimer disease in plasma. NeuroRx 1:226-234.
21. Mayeux R, et al. (1999) Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease. Annals of neurology 46(3):412-416.
22. Vanderstichele H, et al. (2000) Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma. Amyloid 7(4):245-258.
23. Fukumoto H, et al. (2003) Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels. Archives of neurology 60(7):958-964.
24. van Oijen M, Hofman A, Soares HD, Koudstaal PJ, & Breteler MM (2006) Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol 5:655-660.
25. Song MS, Mook-Jung I, Lee HJ, Min JY, & Park MH (2007) Serum anti-amyloid-beta antibodies and Alzheimer’s disease in elderly Korean patients, . J. Int. Med. Res. 35:301-306.
26. Vanderstichele H, et al. (2000) Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma. Amyloid 7:245-258.
27. Mehta PD, et al. (2000) Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease. Archives of neurology 57(1):100-105.
28. Kuo YM, et al. (1999) High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease. Biochemical and biophysical research communications 257(3):787-791.
29. Teunissen CE, de Vente J, Steinbusch HW, & De Bruijn C (2002) Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid Neurobiol. Aging 23:485-508.
30. Cedazo-Minguez A (2007) Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities. Journal of cellular and molecular medicine 11(6):1227-1238.
31. Schiele F, et al. (2000) Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project. Atherosclerosis 152(2):475-488.
32. Panza F, et al. (2003) Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer’s disease patients and centenarians. Neuroreport 14:605-608.
33. Siest G, et al. (2000) Apolipoprotein E polymorphism and serum concentration in Alzheimer’s disease in nine European centres: the ApoEurope study. ApoEurope group. Clin. Chem. Lab. Med. 38:721-730.
34. Nagasaka Y, et al. (2005) A unique gene expression signature discriminates familial Alzheimer’s disease mutation carriers from their wild-type siblings. Proc. Natl. Acad. Sci. USA 102:14854-14859.
35. Grunblatt E, et al. (2007) Comparison analysis of gene expression patterns between sporadic Alzheimer’s and Parkinson’s disease. J. Alzheimers Dis. 12:291-311.
36. Grunblatt E, et al. (2009) Gene expression as peripheral biomarkers for sporadic Alzheimer’s disease. J. Alzheimers Dis. 16:627-634.
37. Mandel P & Metais P (1948) Les acides nucleiques du plasma sanguin chez l’homme. CR Acad. Sci. Paris 142:241-243.
38. Leon SA, Shapiro B, Sklaroff DM, & Yaros MJ (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 37:646-650.
39. Sorenson GD, et al. (1994) Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol. Biomar. Prev. 3:67-71.
40. Vasioukhin V, et al. (1994) Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. British journal of haematology 86(4):774-779.
41. Swarup V & MR. R (2007) Circulating (cell-free) nucleic acids--a promising, non-invasive tool for early detection of several human diseases. FEBS Lett. 581(5):795-799.
42. Allen D, et al. (2004) Role of cell-free plasma DNA as a diagnostic marker for prostate cancer. Annals of the New York Academy of Sciences 1022:76-80.
43. Huang ZH, Li LH, & Hua D (2006) Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients. Cancer letters 243(1):64-70.
44. Sozzi G, et al. (2003) Quantification of free circulating DNA as a diagnostic marker in lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21(21):3902-3908.
45. Chen XQ, Stroun M, & Magnenat JL (1996) Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat. Med 2:1033-1035.
46. Nawroz H, Koch W, Anker P, Stroun M, & Sidransky D (1996) Microsatellite alterations in serum DNA of head and neck cancer patients,. Nat. Med. 2:1035-1037.
47. Taback B, et al. (2004) Circulating DNA microsatellites: molecular determinants of response to biochemotherapy in patients with metastatic melanoma. Journal of the National Cancer Institute 96(2):152-156.
48. Maguire P, et al. (2005) CGH analysis of familial non-BRCA1/BRCA2 breast tumors and mutation screening of a candidate locus on chromosome 17q11.2-12. International journal of molecular medicine 16(1):135-141.
49. Muller HM, et al. (2003) DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer research 63(22):7641-7645.
50. Mori T, et al. (2005) Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(36):9351-9358.
51. Ramirez JL, et al. (2005) 14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(36):9105-9112.
52. Fleischhacker M & Schmidt B (2007) Circulating nucleic acids (CNAs) and cancer--a survey. Biochimica et biophysica acta 1775(1):181-232.
53. Lo YM, et al. (1997) Presence of fetal DNA in maternal plasma and serum. Lancet Neurol 350:485-487.
54. Costa JM, Benachi A, & Gautier E (2002) New strategy for prenatal diagnosis of X-linked disorders. The New England journal of medicine 346(19):1502.
55. Lo YM, et al. (1998) Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. The New England journal of medicine 339(24):1734-1738.
56. Leung TN, Zhang J, Lau TK, Chan LY, & Lo YM (2001) Increased maternal plasma fetal DNA concentrations in women who eventually develop preeclampsia. Clinical chemistry 47(1):137-139.
57. Lau TK, Lo KW, Chan LY, Leung TY, & Lo YM (2000) Cell-free fetal deoxyribonucleic acid in maternal circulation as a marker of fetal-maternal hemorrhage in patients undergoing external cephalic version near term. American journal of obstetrics and gynecology 183(3):712-716.
58. Saito H, Sekizawa A, Morimoto T, Suzuki M, & Yanaihara T (2000) Prenatal DNA diagnosis of a single-gene disorder from maternal plasma. Lancet 356(9236):1170.
59. Amicucci P, Gennarelli M, Novelli G, & Dallapiccola B (2000) Prenatal diagnosis of myotonic dystrophy using fetal DNA obtained from maternal plasma. Clinical chemistry 46(2):301-302.
60. Gonzalez-Gonzalez MC, et al. (2003) Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR. Prenatal diagnosis 23(3):232-234.
61. Chiu RW, et al. (2002) Noninvasive prenatal exclusion of congenital adrenal hyperplasia by maternal plasma analysis: a feasibility study. Clinical chemistry 48(5):778-780.
62. Gonzalez-Gonzalez MC, et al. (2002) Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenatal diagnosis 22(10):946-948.
63. Chiu RW, et al. (2002) Prenatal exclusion of beta thalassaemia major by examination of maternal plasma. Lancet 360(9338):998-1000.
64. Chang CP, et al. (2003) Elevated cell-free serum DNA detected in patients with myocardial infarction. Clinica chimica acta; international journal of clinical chemistry 327(1-2):95-101.
65. Rainer TH, et al. (2003) Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke. Clinical chemistry 49(4):562-569.
66. Lo YM, Rainer TH, Chan LY, Hjelm NM, & Cocks RA (2000) Plasma DNA as a prognostic marker in trauma patients. Clinical chemistry 46(3):319-323.
67. Fox A, et al. (2008) Quantification of circulating cell-free plasma DNA and endothelial gene RNA in patients with burns and relation to acute thermal injury. Burns : journal of the International Society for Burn Injuries 34(6):809-816.
68. Martins GA, Kawamura MT, & Carvalho Mda G (2000) Detection of DNA in the plasma of septic patients. Annals of the New York Academy of Sciences 906:134-140.
69. Rhodes A, Wort SJ, Thomas H, Collinson P, & Bennett ED (2006) Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Critical care 10(2):R60.
70. Tan EM, Schur PH, Carr RI, & Kunkel HG (1966) Deoxybonucleic acid (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. The Journal of clinical investigation 45(11):1732-1740.
71. Galeazzi M, et al. (2003) Dosage and characterization of circulating DNA: present usage and possible applications in systemic autoimmune disorders. Autoimmunity reviews 2(1):50-55.
72. Hamaoui K, Butt A, Powrie J, & Swaminathan R (2004) Concentration of circulating rhodopsin mRNA in diabetic retinopathy. Clinical chemistry 50(11):2152-2155.
73. Shalchi Z, et al. (2008) Retina-specific mRNA in the assessment of diabetic retinopathy. Annals of the New York Academy of Sciences 1137:253-257.
74. Rani S, Clynes M, & O'Driscoll L (2007) Detection of amplifiable mRNA extracellular to insulin-producing cells: potential for predicting beta cell mass and function. Clinical chemistry 53(11):1936-1944.
75. Vasavda N, et al. (2007) Circulating DNA: a potential marker of sickle cell crisis. British journal of haematology 139(2):331-336.
76. Fatouros IG, et al. (2006) Cell-free plasma DNA as a novel marker of aseptic inflammation severity related to exercise overtraining. Clinical chemistry 52(9):1820-1824.
77. Lo YM, et al. (1998) Presence of donor-specific DNA in plasma of kidney and liver-transplant recipients. Lancet 351(9112):1329-1330.
78. Partsalis T, et al. (2006) Evidence of circulating donor genetic material in bone allotransplantation. International journal of molecular medicine 17(6):1151-1155.
79. Gadi VK, Nelson JL, Boespflug ND, Guthrie KA, & Kuhr CS (2006) Soluble donor DNA concentrations in recipient serum correlate with pancreas-kidney rejection. Clinical chemistry 52(3):379-382.
80. Fu YW, Wang WG, Zhou HL, & Cai L (2006) Presence of donor-and-recipient-derived DNA microchimerism in the cell-free blood samples of renal transplantation recipients associates with the acceptance of transplanted kidneys. Asian journal of andrology 8(4):477-482.
81. Fournie GJ, et al. (1995) Plasma DNA as a marker of cancerous cell death. Investigations in patients suffering from lung cancer and in nude mice bearing human tumours. Cancer letters 91(2):221-227.
82. Chen X, et al. (1999) Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin. Cancer Res. 5:2297-2303.
83. Lichtenstein AV, Melkonyan HS, Tomei LD, & Umansky SR (2001) Circulating nucleic acids and apoptosis. Annals of the New York Academy of Sciences 945:239-249.
84. Leon SA, Shapiro B, Sklaroff DM, & Yaros MJ (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer research 37(3):646-650.
85. Stroun M & Anker P (1972) Nucleic acids spontaneously released by living frog auricles. The Biochemical journal 128(3):100P-101P.
86. Stroun M, Lyautey J, Lederrey C, Olson-Sand A, & Anker P (2001) About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clinica chimica acta; international journal of clinical chemistry 313(1-2):139-142.
87. Anker P, Stroun M, & Maurice PA (1975) Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer research 35(9):2375-2382.
88. Cooper EJ, Trautmann ML, & Laskowski M (1950) Occurrence and distribution of an inhibitor for deoxyribonuclease in animal tissues. Proc. Soc. Exp. Biol. Med. 73:219-222.
89. Campello Yurgel V, et al. (2007) Role of plasma DNA as a predictive marker of fatal outcome following severe head injury in males. Journal of neurotrauma 24(7):1172-1181.
90. Ohayon S, et al. (2012) Cell-free DNA as a marker for prediction of brain damage in traumatic brain injury in rats. Journal of neurotrauma 29(2):261-267.
91. Liggett T, et al. (2010) Methylation patterns of cell-free plasma DNA in relapsing-remitting multiple sclerosis. Journal of the neurological sciences 290(1-2):16-21.
92. Baylin SB, et al. (2001) Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Human molecular genetics 10(7):687-692.
93. Rykova EY, Tsvetovskaya GA, Sergeeva GI, Vlassov VV, & Laktionov PP (2008) Methylation-based analysis of circulating DNA for breast tumor screening. Annals of the New York Academy of Sciences 1137:232-235.
94. Vaissiere T, et al. (2009) Quantitative analysis of DNA methylation after whole bisulfitome amplification of a minute amount of DNA from body fluids. Epigenetics : official journal of the DNA Methylation Society 4(4):221-230.
95. Li M, et al. (2009) Sensitive digital quantification of DNA methylation in clinical samples. Nature biotechnology 27(9):858-863.
96. Klose RJ & Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends in biochemical sciences 31(2):89-97.
97. Jaenisch R & Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl:245-254.
98. Bartke T, et al. (2010) Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell 143(3):470-484.
99. Jones PA & Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nature reviews. Genetics 3(6):415-428.
100. Graff J & Mansuy IM (2008) Epigenetic codes in cognition and behaviour. Behavioural brain research 192(1):70-87.
101. Miranda TB & Jones PA (2007) DNA methylation: the nuts and bolts of repression. Journal of cellular physiology 213(2):384-390.
102. Feinberg AP & Tycko B (2004) The history of cancer epigenetics. Nature reviews. Cancer 4(2):143-153.
103. Belinsky SA, et al. (1998) Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proceedings of the National Academy of Sciences of the United States of America 95(20):11891-11896.
104. Wong TS, et al. (2002) High frequency of promoter hypermethylation of the death-associated protein-kinase gene in nasopharyngeal carcinoma and its detection in the peripheral blood of patients. Clinical cancer research : an official journal of the American Association for Cancer Research 8(2):433-437.
105. Goessl C, et al. (2000) Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer research 60(21):5941-5945.
106. Wong IH, et al. (1999) Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer research 59(1):71-73.
107. van der Vaart M & Pretorius PJ (2010) Is the role of circulating DNA as a biomarker of cancer being prematurely overrated? Clinical biochemistry 43(1-2):26-36.
108. Delgado J (2008) Novel epigenetic targets in lymphoproliferative disorders. Current cancer drug targets 8(5):378-391.
109. Sanchez-Pernaute O, Ospelt C, Neidhart M, & Gay S (2008) Epigenetic clues to rheumatoid arthritis. Journal of autoimmunity 30(1-2):12-20.
110. Strickland FM & Richardson BC (2008) Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity 41(4):278-286.
111. Casaccia-Bonnefil P, Pandozy G, & Mastronardi F (2008) Evaluating epigenetic landmarks in the brain of multiple sclerosis patients: a contribution to the current debate on disease pathogenesis. Progress in neurobiology 86(4):368-378.
112. Illingworth R, et al. (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS biology 6(1):e22.
113. Rakyan VK, et al. (2008) An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome research 18(9):1518-1529.
114. Schilling E & Rehli M (2007) Global, comparative analysis of tissue-specific promoter CpG methylation. Genomics 90(3):314-323.
115. Shen L, et al. (2007) Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS genetics 3(10):2023-2036.
116. Brandeis M, Ariel M, & Cedar H (1993) Dynamics of DNA methylation during development. BioEssays : news and reviews in molecular, cellular and developmental biology 15(11):709-713.
117. Eden S & Cedar H (1994) Role of DNA methylation in the regulation of transcription. Current opinion in genetics & development 4(2):255-259.
118. Byun HM, et al. (2009) Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Human molecular genetics 18(24):4808-4817.
119. Akirav EM, et al. (2011) Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proceedings of the National Academy of Sciences of the United States of America 108(47):19018-19023.
120. Tsankova NM, et al. (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature neuroscience 9(4):519-525.
121. Graff J & Mansuy IM (2009) Epigenetic dysregulation in cognitive disorders. The European journal of neuroscience 30(1):1-8.
122. Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447(7143):433-440.
123. Sandberg R, et al. (2000) Regional and strain-specific gene expression mapping in the adult mouse brain. Proceedings of the National Academy of Sciences of the United States of America 97(20):11038-11043.
124. Letwin NE, et al. (2006) Combined application of behavior genetics and microarray analysis to identify regional expression themes and gene-behavior associations. The Journal of neuroscience : the official journal of the Society for Neuroscience 26(20):5277-5287.
125. Lein ES, et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445(7124):168-176.
126. Khaitovich P, et al. (2004) Regional patterns of gene expression in human and chimpanzee brains. Genome research 14(8):1462-1473.
127. Roth RB, et al. (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7(2):67-80.
128. Ladd-Acosta C, et al. (2007) DNA methylation signatures within the human brain. American journal of human genetics 81(6):1304-1315.
129. Ghosh S, et al. (2010) Tissue specific DNA methylation of CpG islands in normal human adult somatic tissues distinguishes neural from non-neural tissues. Epigenetics : official journal of the DNA Methylation Society 5(6):527-538.
130. Mullan M, et al. (1992) A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345-347.
131. Hsiao K, et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284):99-102.
132. Janus C, et al. (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408(6815):979-982.
133. Wyss-Coray T, et al. (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nature medicine 7(5):612-618.
134. McKhaan G DD, Folstein M, Katzman R, Price D, Stadlan EM (Clinical diagnosis of Alzheimer's disease: report of the NINCDA-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
135. Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43(11):2412-2414.
136. Lo YM, et al. (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. American journal of human genetics 62(4):768-775.
137. Qu M, et al. (2011) Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells. Brain research 1368:336-345.
138. Yan JJ, et al. (2001) Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. British journal of pharmacology 133(1):89-96.
139. Stephan A, Laroche S, & Davis S (2001) Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits. The Journal of neuroscience : the official journal of the Society for Neuroscience 21(15):5703-5714.
140. Butt AN & Swaminathan R (2008) Overview of circulating nucleic acids in plasma/serum. Annals of the New York Academy of Sciences 1137:236-242.
141. Urbanova M, Plzak J, Strnad H, & Betka J (2010) Circulating nucleic acids as a new diagnostic tool. Cellular & molecular biology letters 15(2):242-259.
142. McKhann G, et al. (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34(7):939-944.
143. Lin KN, et al. (2002) Cutoff scores of the cognitive abilities screening instrument, Chinese version in screening of dementia. Dementia and geriatric cognitive disorders 14(4):176-182.
144. Tsai RC, Lin KN, Wu KY, & Liu HC (2004) Improving the screening power of the cognitive abilities screening instrument, Chinese version. Dementia and geriatric cognitive disorders 18(3-4):314-320.
145. Liu HC, et al. (2002) Performance on the cognitive abilities screening instrument at different stages of Alzheimer's disease. Dementia and geriatric cognitive disorders 13(4):244-248.
146. Qin ZX, Zhu HY, & Hu YH (2009) Effects of lysophosphatidylcholine on beta-amyloid-induced neuronal apoptosis. Acta pharmacologica Sinica 30(4):388-395.
147. Lesne S, et al. (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352-357.
148. Lesne S, Kotilinek L, & Ashe KH (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151(3):745-749.
149. Cheng IH, et al. (2007) Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. The Journal of biological chemistry 282(33):23818-23828.
150. Lambert MP, et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the United States of America 95(11):6448-6453.
151. Resende R, Ferreiro E, Pereira C, & Resende de Oliveira C (2008) Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death. Neuroscience 155(3):725-737.
152. Reese LC, Zhang W, Dineley KT, Kayed R, & Taglialatela G (2008) Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Aging cell 7(6):824-835.
153. Gong Y, et al. (2003) Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings of the National Academy of Sciences of the United States of America 100(18):10417-10422.
154. Barry AE, et al. (2011) Alzheimer's disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(20):7259-7263.
155. Li S, et al. (2011) Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(18):6627-6638.
156. Klyubin I, et al. (2008) Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. The Journal of neuroscience : the official journal of the Society for Neuroscience 28(16):4231-4237.
157. Sai S, et al. (2007) Quantification of plasma cell-free DNA in patients with gastric cancer. Anticancer research 27(4C):2747-2751.
158. Sozzi G, et al. (2001) Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer research 61(12):4675-4678.
159. Catarino R, et al. (2008) Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA and cell biology 27(8):415-421.
160. Sherry NA, et al. (2006) Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55(12):3238-3245.
161. Basadonna G, Montorsi F, Kakizaki K, & Merrell RC (1988) Cyclosporin A and islet function. American journal of surgery 156(3 Pt 1):191-193.
162. Berney T, et al. (2006) Detection of insulin mRNA in the peripheral blood after human islet transplantion predicts deterioration of metabolic control. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 6(7):1704-1711.
163. Chapman PF, et al. (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nature neuroscience 2(3):271-276.
164. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, & Hyman BT (1997) APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. Journal of neuropathology and experimental neurology 56(9):965-973.
165. Bianchi SL, et al. (2008) Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiology of aging 29(7):1002-1010.
166. Tan L, et al. (2013) A systematic analysis of genomic changes in Tg2576 mice. Molecular neurobiology 47(3):883-891.
167. Calkins MJ, Manczak M, Mao P, Shirendeb U, & Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Human molecular genetics 20(23):4515-4529.
168. Giacona MB, et al. (1998) Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas 17(1):89-97.
169. Jahr S, et al. (2001) DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer research 61(4):1659-1665.
170. Suzuki N, Kamataki A, Yamaki J, & Homma Y (2008) Characterization of circulating DNA in healthy human plasma. Clinica chimica acta; international journal of clinical chemistry 387(1-2):55-58.
171. Choi JJ, Reich CF, 3rd, & Pisetsky DS (2004) Release of DNA from dead and dying lymphocyte and monocyte cell lines in vitro. Scandinavian journal of immunology 60(1-2):159-166.
172. Behl C, Davis JB, Klier FG, & Schubert D (1994) Amyloid beta peptide induces necrosis rather than apoptosis. Brain research 645(1-2):253-264.
173. Akiyama H, et al. (2000) Inflammation and Alzheimer's disease. Neurobiology of aging 21(3):383-421.
174. Lim GP, et al. (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 20(15):5709-5714.
175. Frautschy SA, et al. (1998) Microglial response to amyloid plaques in APPsw transgenic mice. The American journal of pathology 152(1):307-317.
176. Benzing WC, et al. (1999) Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiology of aging 20(6):581-589.
177. Sheng JG, et al. (2003) Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiology of disease 14(1):133-145.
178. Neher JJ, et al. (2011) Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. Journal of immunology 186(8):4973-4983.
179. Obeid LM, Linardic CM, Karolak LA, & Hannun YA (1993) Programmed cell death induced by ceramide. Science 259(5102):1769-1771.
180. Wajant H, Pfizenmaier K, & Scheurich P (2003) Tumor necrosis factor signaling. Cell death and differentiation 10(1):45-65.
181. Ashe KH & Zahs KR (2010) Probing the biology of Alzheimer's disease in mice. Neuron 66(5):631-645.
182. Ashe KH (2006) Molecular basis of memory loss in the Tg2576 mouse model of Alzheimer's disease. Journal of Alzheimer's disease : JAD 9(3 Suppl):123-126.
183. Monuki ES, Porter FD, & Walsh CA (2001) Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 32(4):591-604.
184. Mangale VS, et al. (2008) Lhx2 selector activity specifies cortical identity and suppresses hippocampal organizer fate. Science 319(5861):304-309.
185. Bulchand S, Subramanian L, & Tole S (2003) Dynamic spatiotemporal expression of LIM genes and cofactors in the embryonic and postnatal cerebral cortex. Developmental dynamics : an official publication of the American Association of Anatomists 226(3):460-469.
186. Subramanian L, et al. (2011) Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus. Proceedings of the National Academy of Sciences of the United States of America 108(27):E265-274.
187. Sanuki R, et al. (2011) miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nature neuroscience 14(9):1125-1134.