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.
Get full access to this article
View all access options for this article.
References
1.
ConnorB, YoungD, YanQ, FaullRL, SynekB, DragunowM. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res Mol Brain Res, 1997; 49:71–81.
PanzaF, FrisardiV, ImbimboBP, D'OnofrioG, PietrarossaG, SeripaD, PilottoA, SolfrizziV. Bapineuzumab: Anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. Immunotherapy, 2010; 2:767–782.
4.
MurerMG, BoissiereF, YanQ, HunotS, VillaresJ, FaucheuxB, AgidY, HirschE, Raisman-VozariR. An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease. Neuroscience, 1999; 88:1015–1032.
5.
SiegelGJ, ChauhanNB. Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res Brain Res Rev, 2000; 33:199–227.
6.
ElliottE, AtlasR, LangeA, GinzburgI. Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 kinase signalling mechanism. Eur J Neurosci, 2005; 22:1081–1089.
7.
ArancibiaS, SilholM, MoulièreF, MeffreJ, HôllingerI, MauriceT, Tapia-ArancibiaL. Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo apoptosis. Trends Cell Biol, 2001; 11:6–10.
8.
MaisonpierrePC, Le BeauMM, EspinosaR. Human and rat brain-derived neurotrophic factor and neurotrophin-3: Genes structures, distribution and chromosomal localizations. Genomics, 1991; 10:558–568.
9.
VentrigliaM, Bocchio ChiavettoL, BenussiL, BinettiG, ZanettiO, RivaMA, GennarelliM. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry, 2002; 7:136–137.
10.
EikelenboomP, VeerhuisR, FamilianA, HoozemansJJ, van GoolWA, RozemullerAJ. Neuroinflammation in plaque and vascular beta-amyloid disorders: Clinical and therapeutic implications. Neurodegener Dis, 2008; 5:190–193.
11.
GriffinWS. Inflammation and neurodegenerative diseases. Am J Clin Nutr, 2006; 83:470S–474S.
12.
ShepherdCE, ThielE, McCannH, HardingAJ, HallidayGM. Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies. Arch Neurol, 2000; 57:817–822.
13.
ArnaudL, RobakisNK, Figueiredo-PereiraME. It may take inflammation, phosphorylation and ubiquitination to ‘tangle’ in Alzheimer's disease. Neurodegener Dis, 2006; 3:313–319.
14.
GorlovoyP, LarionovS, PhamTT, NeumannH. Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J, 2009; 23:2502–2513.
15.
In t' VeldBA, RuitenbergA, HofmanA, LaunerLJ, van DuijnCM, StijnenT, BretelerMM, StrickerBH. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med, 2001; 345:1515–1521.
16.
McGeerPL, McGeerEG. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol Aging, 2007; 28:639–647.
17.
StewartWF, KawasC, CorradaM, MetterEJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology, 1997; 48:626–632.
18.
KunugiH, UekiA, OtsukaM, IsseK, HirasawaH, KatoN, abikaT, KobayashiS, NankoS. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatry, 2001; 6:83–86.
19.
RiemenschneiderM, SchwarzS, WagenpfeilS, DiehlJ, MullerU, ForstlH, KurzA. A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the apolipoprotein E epsilon4 allele. Mol Psychiatry, 2002; 7:782–785.
20.
XiaoZ, LiuW, GaoK, WanQ, YangC, WangH, WangX, WangG, LiuZ. Interaction between CRHR1 and BDNF genes increases the risk of recurrent major depressive disorder in Chinese population. PLoS One, 2011; 6:e28733.
21.
CarusoC, FranceschiC, LicastroF. Genetics of neurodegenerative disorders. N Engl J Med, 2003; 349:193–194.
22.
LicastroF, ChiappelliM. Brain immune responses cognitive decline and dementia: Relationship with phenotype expression and genetic background. Mech Ageing Dev, 2003; 124:539–548.
23.
SeripaD, MateraMG, Dal FornoG, GravinaC, MasulloC, DanieleA, BinettiG, BonviciniC, SquittiR, PalermoMT, DavisDG, AntuonoP, WeksteinDR, DobrinaA, GennarelliM, FazioVM. Genotypes and haplotypes in the IL-1 gene cluster: Analysis of two genetically and diagnostically distinct groups of Alzheimer patients. Neurobiol Aging, 2005; 26:455–464.
24.
SklarP, GabrielSB, McInnisMG, BennettP, LimYM, TsanG, SchaffnerS, KirovG, JonesI, OwenM, CraddockN, DePauloJR, LanderES. Family based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol Psychiatry, 2002; 7:579–593.
LyketsosCG, LopezO, JonesB, FitzpatrickAL, BreitnerJ, DeKoskyS. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the cardiovascular health study. JAMA, 2002; 288:1475–1483.
28.
SteinbergM, ShaoH, ZandiP, LyketsosCG, Welsh-BohmerKA, NortonMC, BreitnerJC, SteffensDC, TschanzJT. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache county study. Int J Geriatr Psychiatry, 2008; 23:170–177.
29.
LeeHB, LyketsosCG. Depression in Alzheimer's disease: Heterogeneity and related issues. Biol Psychiatry, 2003; 54:353–362.
30.
KaregeF, PerretG, BondolfiG, SchwaldM, BertschyG, AubryJM. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res, 2002; 15:143–148.
31.
ChenB, DowlatshahiD, MacQueenGM, WangJF, YoungLT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry, 2001; 15:260–265.
32.
LaskeC, StranskyE, LeyheT, EschweilerGW, MaetzlerW, WittorfA, SoekadarS, RichartzE, KoehlerN, BartelsM, BuchkremerG, SchottK. BDNF serum and CSF concentrations in Alzheimer's disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res, 2007; 41:387–394.
33.
CastrenE, ThoenenH, LindholmD. 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. Neuroscience, 1995; 64:71–80.
34.
HoferM, PagliusiSR, HohnA, LeibrockJ, BardeYA. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J, 1990; 9:2459–2464.
35.
MaisonpierrePC, BelluscioL, FriedmanB, AldersonRF, WiegandSJ, FurthME, LindsayRM, YancopoulosGD. NT-3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression. Neuron, 1990; 5:501–509.
36.
SchinderAF, PooM. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci, 2000; 23:639–645.
37.
FujimuraH, AltarCA, ChenR, NakamuraT, NakahashiT, KambayashiJ, SunB, TandonNN. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost, 2002; 87:728–734.
38.
GielenA, KhademiM, MuhallabS, OlssonT, PiehlF. Increased brain derived neurotrophic factor expression in white blood cells of relapsing-remitting multiple sclerosis patients. Scand J Immunol, 2003; 57:493–497.
39.
KerschensteinerM, GallmeierE, BehrensL, LealVV, MisgeldT, KlinkertWE, KolbeckR, HoppeE, Oropeza-WekerleRL, BartkeI, StadelmannC, LassmannH, WekerleH, HohlfeldR. 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?J Exp Med, 1999; 189:865–870.
40.
EganMF, KojimaM, CallicottJH, GoldbergTE, KolachanaBS, BertolinoA, ZaitsevE, GoldB, GoldmanD, DeanM, LuB, WeinbergerDR. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 2003; 112:257–269.
41.
HwangJP, TsaiSJ, HongCJ, YangCH, LirngJF, YangYM. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging, 2006; 27:1834–1837.
42.
SchumacherJ, JamraRA, BeckerT, OhlraunS, KloppN, BinderEB, SchulzeTG, DeschnerM, SchmalC, HofelsS, ZobelA, IlligT, ProppingP, HolsboerF, RietschelM, NothenMM, CichonS. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry, 2005; 58:307–314.
43.
ChoiMJ, KangRH, LimSW, OhKS, LeeMS. Brain derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res, 2006; 1118:176–182.
44.
KimJM, StewartR, KimSW, YangSJ, ShinIS, KimYH, YoonJS. BDNF genotype potentially modifying the association between incident stroke and depression. Neurobiol Aging, 2008; 29:789–792.
45.
TsaiSJ, HongCJ, LiuHC, LiuTY, HsuLE, LinCH. Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer's disease and age of onset. Neuropsychobiology, 2004; 49:10–12.
46.
BorroniB, ArchettiS, CostanziC, GrassiM, FerrariM, RadeghieriA, CaimiL, CaltagironeC, Di LucaM, PadovaniA. Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression. Neurobiol Aging, 2009; 30:1406–1412.
47.
ZhangL, FangY, ZengZ, LianY, WeiJ, ZhuH, JiaY, ZhaoX, XuY. BDNF gene polymorphisms are associated with Alzheimer's disease-related depression and antidepressant response. J Alzheimers Dis, 2011; 26:523–530.
48.
CombarrosO, InfanteJ, LlorcaJ, BercianoJ. Polymorphism at codon 66 of the brain-derived neurotrophic factor gene is not associated with sporadic Alzheimer's disease. Dement Geriatr Cogn Disord, 2004; 18:55–58.
49.
BagnoliS, NacmiasB, TeddeA, GuarnieriBM, CelliniE, PetruzziC, BartoliA, OrtenziL, SorbiS. Brain-derived neurotrophic factor genetic variants are not susceptibility factors to Alzheimer's disease in Italy. Ann Neurol, 2004; 55:447–448.
50.
KambohMI. Molecular genetics of late-onset Alzheimer's disease. Ann Hum Genet, 2004; 68:381–404.
51.
NishimuraAL, OliveiraJR, Mitne-NetoM, GuindaliniC, NitriniR, BahiaVS, de Brito-MarquesPR, OttoPA, ZatzM. Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer's disease (LOAD) in Brazilian patients. J Mol Neurosci, 2004; 22:257–260.
52.
DesaiP, NebesR, DeKoskyST, KambohMI. 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. Neurosci Lett, 2005; 379:229–234.
53.
ParsianA, SinhaR, RacetteB, ZhaoJH, PerlmutterJS. Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson's disease. Parkinsonism Relat Disord, 2004; 10:213–219.
54.
SzekeresG, JuhászA, RimanóczyA, KériS, JankaZ. The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia. Schizophr Res, 2003; 65:15–18.
55.
GrünblattE, ZehetmayerS, BartlJ, LöfflerC, WichartI, RainerMK, JungwirthS, BauerP, DanielczykW, TraglKH, RiedererP, FischerP. Genetic risk factors and markers for Alzheimer's disease and/or depression in the VITA study. J Psychiatr Res, 2009; 43:298–308.
56.
BodnerSM, BerrettiniW, van DeerlinV, BennettDA, WilsonRS, TrojanowskiJQ, ArnoldSE. Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet, 2005; 134:1–5.
57.
SaarelaMS, LehtimakiT, RinneJO, HuhtalaH, RontuR, HervonenA, RoyttaM, AhonenJP, MattilaKM. No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer's or Parkinson's disease. Folia Neuropathol, 2006; 44:12–16.
58.
AgartzI, SedvallGC, TereniusL, KulleB, FrigessiA, HallH, JönssonEG. BDNF gene variants and brain morphology in schizophrenia. Am J Med Genet B Neuropsychiatr Genet, 2006; 141B:513–523.
59.
MignoneF, GissiC, LiuniS, PesoleG. Untranslated regions of mRNAs. Genome Biol, 2002; 3REVIEWS0004.
60.
ModarresiF, FaghihiMA, Lopez-ToledanoMA, FatemiRP, MagistriM, BrothersSP, van der BrugMP, WahlestedtC. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol, 2012; 30:453–459.
