Brain-derived neurotrophic factor gene variants and Alzheimer disease: an association study in an Alzheimer disease Italian population.

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival during development and protects neurons from insults of various kinds. Changes in production of BDNF have been reported in differing neurodegenerative pathologies and, in particular, in Alzheimer disease (AD). We studied 200 AD patients and 408 healthy controls for BDNF Val66Met(G196A) polymorphism, 200AD and 384 healthy controls for BDNF 270 C/T polymorphism, and 200AD and 393 healthy controls for BDNF 11757 G/C polymorphism by restriction fragment length polymorphism (RFLP) and real-time PCR. Our results indicated that the 11757 G/C BDNF polymorphism was significantly associated with AD. A statistically significant increase of GG genotype frequency in AD versus healthy subjects (p=0.0331) was observed, whereas the CG genotype demonstrates a statistically significant decrease of frequency in AD patients versus controls (p=0.0194). We focused our attention on haplotype reconstruction: A statistically significant decrease of the TAC haplotype frequency in AD patients versus healthy controls group (p=0.005) and a statistically significant increase of the CAC haplotype frequency in patients versus control (p=0.019) was demonstrated. We then studied the haplotype frequencies dividing patients according to gender. A statistically significant increase of the CAC haplotype in the male AD group compared with male healthy controls (p=0.041) was found, whereas a statistically significant decrease of TAC haplotype frequency in AD females versus healthy females (p=0.005) and a statistically significant increase of CAC haplotype frequency in female patients versus healthy females (p=0.019) was noticed. We propose that these haplotypes could be a further effective marker for AD.

[1]  C. Wahlestedt,et al.  Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation , 2012, Nature Biotechnology.

[2]  Wanhong Liu,et al.  Interaction between CRHR1 and BDNF Genes Increases the Risk of Recurrent Major Depressive Disorder in Chinese Population , 2011, PloS one.

[3]  F. Panza,et al.  Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. , 2010, Immunotherapy.

[4]  C. Caruso,et al.  Gender-related immune-inflammatory factors, age-related diseases, and longevity. , 2010, Rejuvenation research.

[5]  C. Caltagirone,et al.  Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression , 2009, Neurobiology of Aging.

[6]  H. Neumann,et al.  Accumulation of tau induced in neurites by microglial proinflammatory mediators , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  F. Mouliere,et al.  Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats , 2008, Neurobiology of Disease.

[8]  R. Stewart,et al.  BDNF genotype potentially modifying the association between incident stroke and depression , 2008, Neurobiology of Aging.

[9]  R. Veerhuis,et al.  Neuroinflammation in Plaque and Vascular β-Amyloid Disorders: Clinical and Therapeutic Implications , 2008, Neurodegenerative Diseases.

[10]  Constantine G Lyketsos,et al.  Point and 5‐year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study , 2008, International journal of geriatric psychiatry.

[11]  S. Soekadar,et al.  BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls. , 2007, Journal of psychiatric research.

[12]  Patrick L. McGeer,et al.  NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies , 2007, Neurobiology of Aging.

[13]  N. Robakis,et al.  It May Take Inflammation, Phosphorylation and Ubiquitination to ‘Tangle’ in Alzheimer’s Disease , 2007, Neurodegenerative Diseases.

[14]  Jiing-Feng Lirng,et al.  The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression , 2006, Neurobiology of Aging.

[15]  Se-Won Lim,et al.  Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder , 2006, Brain Research.

[16]  Arnoldo Frigessi,et al.  BDNF gene variants and brain morphology in schizophrenia , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[17]  Erik G. Jönsson,et al.  Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: An association study , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[18]  T. Lehtimäki,et al.  No association between the brain-derived neurotrophic factor 196G>A or 270C>T polymorphisms and Alzheimer’s or Parkinson’s disease , 2006 .

[19]  W. Griffin,et al.  Inflammation and neurodegenerative diseases. , 2006, The American journal of clinical nutrition.

[20]  E. Elliott,et al.  Brain‐derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI‐3Kinase signalling mechanism , 2005, The European journal of neuroscience.

[21]  S. Cichon,et al.  Evidence for a Relationship Between Genetic Variants at the Brain-Derived Neurotrophic Factor (BDNF) Locus and Major Depression , 2005, Biological Psychiatry.

[22]  S. DeKosky,et al.  Investigation of the effect of brain-derived neurotrophic factor (BDNF) polymorphisms on the risk of late-onset Alzheimer's disease (AD) and quantitative measures of AD progression , 2005, Neuroscience Letters.

[23]  D. Bennett,et al.  Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[24]  D. Davis,et al.  Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients , 2005, Neurobiology of Aging.

[25]  M. Kamboh,et al.  Molecular Genetics of Late‐Onset Alzheimer's Disease , 2004, Annals of human genetics.

[26]  O. Combarros,et al.  Polymorphism at Codon 66 of the Brain-Derived Neurotrophic Factor Gene Is Not Associated with Sporadic Alzheimer’s Disease , 2004, Dementia and Geriatric Cognitive Disorders.

[27]  J. Perlmutter,et al.  Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson's disease. , 2004, Parkinsonism & related disorders.

[28]  S. Sorbi,et al.  Brain‐derived neurotrophic factor genetic variants are not susceptibility factors to Alzheimer's disease in Italy , 2004, Annals of neurology.

[29]  S. Tsai,et al.  Association Analysis of Brain-Derived Neurotrophic Factor Val66Met Polymorphisms with Alzheimer’s Disease and Age of Onset , 2004, Neuropsychobiology.

[30]  S. Kéri,et al.  The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia , 2003, Schizophrenia Research.

[31]  Constantine G Lyketsos,et al.  Depression in Alzheimer’s disease: heterogeneity and related issues , 2003, Biological Psychiatry.

[32]  C. Franceschi,et al.  Genetics of neurodegenerative disorders. , 2003, The New England journal of medicine.

[33]  T. Olsson,et al.  Increased Brain‐Derived Neurotrophic Factor Expression in White Blood Cells of Relapsing–Remitting Multiple Sclerosis Patients , 2003, Scandinavian journal of immunology.

[34]  F. Licastro,et al.  Brain immune responses cognitive decline and dementia: relationship with phenotype expression and genetic background , 2003, Mechanisms of Ageing and Development.

[35]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[36]  C. Lyketsos,et al.  Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. , 2002, JAMA.

[37]  Ruoyan Chen,et al.  Brain-derived Neurotrophic Factor Is Stored in Human Platelets and Released by Agonist Stimulation , 2002, Thrombosis and Haemostasis.

[38]  J. Aubry,et al.  Decreased serum brain-derived neurotrophic factor levels in major depressed patients , 2002, Psychiatry Research.

[39]  C. Gissi,et al.  Untranslated regions of mRNAs , 2002, Genome Biology.

[40]  G. MacQueen,et al.  Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication , 2001, Biological Psychiatry.

[41]  Mu-ming Poo,et al.  The neurotrophin hypothesis for synaptic plasticity , 2000, Trends in Neurosciences.

[42]  G. Donnan,et al.  Reduced BDNF mRNA Expression in the Parkinson's Disease Substantia Nigra , 2000, Experimental Neurology.

[43]  G. Siegel,et al.  Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain , 2000, Brain Research Reviews.

[44]  G. Halliday,et al.  Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies. , 2000, Archives of neurology.

[45]  Hans Lassmann,et al.  Activated Human T Cells, B Cells, and Monocytes Produce Brain-derived Neurotrophic Factor In Vitro and in Inflammatory Brain Lesions: A Neuroprotective Role of Inflammation? , 1999, The Journal of experimental medicine.

[46]  Y. Agid,et al.  An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease , 1999, Neuroscience.

[47]  R. Faull,et al.  Brain-derived neurotrophic factor is reduced in Alzheimer's disease. , 1997, Brain research. Molecular brain research.

[48]  W F Stewart,et al.  Risk of Alzheimer's disease and duration of NSAID use , 1997, Neurology.

[49]  E. Castrén,et al.  Brain-derived neurotrophic factor messenger RNA is expressed in the septum, hypothalamus and in adrenergic brain stem nuclei of adult rat brain and is increased by osmotic stimulation in the paraventricular nucleus , 1995, Neuroscience.

[50]  S M de la Monte,et al.  Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. , 1991, Genomics.

[51]  L. Belluscio,et al.  NT-3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression , 1990, Neuron.

[52]  Y. Barde,et al.  Regional distribution of brain‐derived neurotrophic factor mRNA in the adult mouse brain. , 1990, The EMBO journal.

[53]  Xinyu Zhao,et al.  BDNF gene polymorphisms are associated with Alzheimer's disease-related depression and antidepressant response. , 2011, Journal of Alzheimer's disease : JAD.

[54]  Sonja Zehetmayer,et al.  Genetic risk factors and markers for Alzheimer's disease and/or depression in the VITA study. , 2009, Journal of psychiatric research.

[55]  M. Zatz,et al.  Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer’s disease (LOAD) in Brazilian patients , 2007, Journal of Molecular Neuroscience.

[56]  J. Rinne,et al.  No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer's or Parkinson's disease. , 2006, Folia neuropathologica.

[57]  Hans Förstl,et al.  A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E ε4 allele , 2002, Molecular Psychiatry.

[58]  M. Riva,et al.  Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease , 2002, Molecular Psychiatry.

[59]  S. Gabriel,et al.  Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus , 2002, Molecular Psychiatry.

[60]  N. Kato,et al.  A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease , 2001, Molecular Psychiatry.

[61]  D. Green,et al.  Stress management - heat shock protein-70 and the regulation of apoptosis. , 2001, Trends in cell biology.

[62]  A. Lbert,et al.  Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease , 2022 .