The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression

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Abstract

Transforming growth factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against β-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in Alzheimer's disease (AD) brain. TGF-β1 is also involved in the pathogenesis of depressive disorders, which may occur in 30–40% of AD patients. The TGF-β1 gene contains single nucleotide polymorphisms (SNPs) at codon + 10 (T/C) and + 25 (G/C), which are known to influence the level of expression of TGF-β1.

We investigated TGF-β1 + 10 (T/C) and + 25 (G/C) SNPs and allele frequencies in 131 sporadic AD patients and in 135 healthy age- and sex-matched controls. Genotypes of the TGF-β1 SNPs at codon + 10 (T/C) and + 25 (G/C) did not differ between AD patients and controls, whereas the allele frequencies of codon + 10 polymorphism showed a significant difference (P = 0.0306). We also found a different distribution of the + 10 (C/C) phenotype (continuity-corrected χ2 test with one degree of freedom = 4.460, P = 0.0347) between late onset AD (LOAD) patients and controls (P = 0.0126), but not between early onset AD (EOAD) patients and controls. In addition, the presence of the C/C genotype increased the risk of LOAD regardless of the status of apolipoprotein E4 (odds ratio [OR] = 2.34; 95% CI = 1.19–4.59). Compared to patients bearing the T/T and C/T polymorphisms, LOAD TGF-β1 C/C carriers also showed > 5-fold risk to develop depressive symptoms independently of a history of depression (OR = 5.50; 95% CI = 1.33–22.69). An association was also found between the TGF-β1 C/C genotype and the severity of depressive symptoms (HAM-D17  14) (P < 0.05). These results suggest that the CC genotype of the TGF-β1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by senile plaques containing β-amyloid protein (Aβ) and neurofibrillary tangles (NFT) riched in hyperphosphorylated tau protein (Hardy and Selkoe, 2002). Aβ exerts a primary role in the cascade of events leading to neuronal death in AD (Walsh and Selkoe, 2007). Oligomeric species composed of aggregated Aβ are believed to exert toxic effects on synaptic and cellular functions, finally leading to neurodegeneration (Cerpa et al., 2008). It has been hypothesized that neurotoxicity of Aβ oligomers in vivo is limited by the presence of neurotrophic factors that may be deficient in the AD brain (Castren and Tanila, 2006). One possible candidate is transforming-growth-factor β1 (TGF-β1) (Wyss-Coray, 2006, Caraci et al., 2009).

Recently, a specific impairment of TGF-β1 signaling has been demonstrated in the AD brain. Tesseur et al. (2006) have found that the expression of TGF-β type II receptor in neurons is reduced early in the course of AD. AD patients also showed a reduction in the plasma levels of the active (25 kDa) and inactive (50 kDa) forms of TGF-β1 (Mocali et al., 2004, Juraskova et al., 2010), and a reduced secretion of TGF-β1 secretion from circulating peripheral blood mononuclear cells (Luppi et al., 2009).

TGF-β1 protein levels are predominantly under genetic control, and the TGF-β1 gene, located on chromosome 19q13.1–3, contains several single nucleotide polymorphisms (SNPs) upstream and in the transcript region which may affect protein levels (Awad et al., 1998, Grainger et al., 1999, Perrey et al., 1999). SNPs at codons + 10 (T(C) and + 25 (G/C), that reduce TGF-β1 expression, have recently been associated with an increased conversion from mild cognitive impairment (MCI) into AD (Arosio et al., 2007).

TGF-β1 is also involved in the pathogenesis of depression (Adler et al., 2006, Caraci et al., 2010a) and depressive disorders occur in about 30–40% of AD patients influencing the clinical evolution of the disease (Lyketsos et al., 1997, Starkstein et al., 2005, Shim and Yang, 2006). No study has investigated the possible association of the TGF-β1 gene with AD-related depression.

Based on these observations, this study was designed to examine the association of the + 10 (T/C) and + 25 (G/C) polymorphisms of the TGF-β1 gene with AD and the influence of this polymorphism on the onset of AD-related depression.

Section snippets

Subjects

A total of 266 subjects, including 131 AD patients (75 F/56 M; mean age 69.9 ± 9.34 S.D.), were recruited at the IRCCS Oasi Maria S.S. of Troina (Italy) and the diagnosis of probable AD was made following the NINCDS-ADRDA criteria (McKhann et al., 1984). No patients had autosomal dominant familiar forms of AD. The 135 control subjects (71 F/64 M; mean age 70.8 ± 10.5 S.D.) had no cognitive impairment and/or family history of AD. The mini-mental state examination (MMSE) score was > 28 in all controls.

Results

Patients and controls had no significant difference in sex ratio and age, with 75 (57.3%, 95% C.I. 35.1–48.4%) females in the AD group compared to 71 (52.6%, 95% C.I. 44.2–60.8%) in the control group (P = 0.4452). The distributions of genotypes from the TGF-β1 and ApoE polymorphisms were all in Hardy–Weinberg equilibrium. Genotype frequencies of the + 10 (T/C) polymorphism of the TGF-β1 gene were not significantly different between AD patients and controls (Table 1), whereas the allele frequencies

Discussion

Chronic inflammation and an impairment of neurotrophin signaling play a central role in the pathogenesis of AD (Di Rosa et al., 2006, Rojo et al., 2008, Caraci et al., 2010a). Increased levels of proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, have been found in the plasma and CSF of AD patients (Cacabelos et al., 1991, Singh and Guthikonda, 1997). Inflammatory responses, elicited by Aβ oligomers on microglial cells, occur early in AD (Okello et al., 2009), and genetic polymorphisms of

Role of the funding source

No sponsor acted in any phase of the present study. Funding for this study was provided by the Italian Ministry of Health (“Ricerca Corrente” and “Cinque per Mille”).

Contributors

Authors F Caraci and P Bosco designed the study and wrote the protocol. Author M Signorelli managed the literature searches and analyzed HAM-D17 scores in AD patients. Authors R Spada, F Cosentino recruited AD patients at the IRCCS Oasi Maria S.S. of Troina. Authors G Toscano, C Bonforte, S Muratore, G Prestianni, S Panerai, MC Giambirtone, E Gulotta rated depressive symptoms in LOAD patients. Author P Bosco undertook the statistical analysis. C Romano, MG Salluzzo performed most of the

Conflict of interest

No conflict of interest exists for any the Authors of the present paper.

Acknowledgments

No acknowledgements.

References (77)

  • J.C. Lambert et al.

    Genetics of Alzheimer's disease: new evidences for an old hypothesis?

    Curr. Opin. Genet. Dev.

    (2011)
  • K.M. Lee et al.

    The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive Disorder

    Int. Immunopharmacol.

    (2006)
  • C. Luppi et al.

    Growth factors decrease in subjects with mild to moderate Alzheimer's disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS)

    Arch. Gerontol. Geriatr.

    (2009)
  • A. Mocali et al.

    Increased plasma levels of soluble CD40, together with the decrease of TGF beta 1,as possible differential markers of Alzheimer disease

    Exp. Gerontol.

    (2004)
  • M. Motta et al.

    Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression

    Immunol. Lett.

    (2007)
  • M.G. Murer et al.

    Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease

    Prog. Neurobiol.

    (2001)
  • A.M. Myint et al.

    Th1, Th2, and Th3 cytokine alterations in major depression

    J. Affect. Disord.

    (2005)
  • R. Peila et al.

    A TGF-beta1 polymorphism association with dementia and neuropathologies: the HAAS

    Neurobiol. Aging

    (2007)
  • C. Perrey et al.

    ARMS-PCR methodologies to determine IL-10, TNF-alpha, TNF-beta and TGF-beta1 gene polymorphisms

    Transplant. Immunol.

    (1999)
  • S. Redondo et al.

    TGF-beta1: a novel target for cardiovascular pharmacology

    Cytokine Growth Factor. Rev.

    (2007)
  • L.E. Rojo et al.

    Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease

    Arch. Med. Res.

    (2008)
  • Y.S. Shim et al.

    Depression as prognostic factor: 6 months follow-up in a geriatric institution

    Arch. Gerontol. Geriatr.

    (2006)
  • V.K. Singh et al.

    Circulating cytokines in Alzheimer's disease

    J. Psychiatr. Res.

    (1997)
  • M. Van Oijen et al.

    Polymorphisms in the interleukin 6 and transforming growth factor beta1 gene and risk of dementia. The Rotterdam Study

    Neurosci. Lett.

    (2006)
  • D. Vivien et al.

    Transforming growth factor-β signalling in brain disorder

    Cytokine Growth Factor Rev.

    (2006)
  • S. Wuwongse et al.

    The putative neurodegenerative links between depression and Alzheimer's disease

    Prog. Neurobiol.

    (2010)
  • U.C. Adler et al.

    Inflammatory aspects of depression

    Inflamm. Allergy Drug Targets

    (2006)
  • R. Aharoni et al.

    The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • G. Anello et al.

    Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease

    Neuroreport

    (2004)
  • L. Araria-Goumidi et al.

    Association study of three polymorphisms of TGF-beta1 gene with Alzheimer's disease

    J. Neurol. Neurosurg. Psychiatry

    (2002)
  • M.R. Awad et al.

    Genotypic variation in the transforming growth factor-b1 gene

    Transplantation

    (1998)
  • E. Boerwinkle et al.

    The use of measured genotype information in the analysis of quantitative phenotypes in man. III. Simultaneous estimation of the frequencies and effects of the apolipoprotein E polymorphism and residual polygenetic effects on cholesterol, betalipoprotein and triglyceride levels

    Ann. Hum. Genet.

    (1987)
  • B. Borroni et al.

    Genetic susceptibility to behavioural and psychological symptoms in Alzheimer disease

    Curr. Alzheimer Res.

    (2010)
  • P. Bosco et al.

    Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease

    J. Neurol. Neurosurg. Psychiatry

    (2004)
  • M. Brazzelli et al.

    A neuropsychological instrument adding to the description of patients with suspected cortical dementia: the Milan overall dementia assessment

    J. Neurol. Neurosurg. Psychiatry

    (1994)
  • R. Cacabelos et al.

    Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer's disease and neurological disorders

    Methods Find. Exp. Clin. Pharmacol.

    (1991)
  • F. Caraci et al.

    TGF-beta1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease

    CNS Neurosci. Ther.

    (2009)
  • F. Caraci et al.

    Targeting group-II metabotropic glutamate receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies {beta}-amyloid toxicity in cultured neurons whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective

    Mol. Pharmacol.

    (2010)
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    The first two authors equally contributed to this article.

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