The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression
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.
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The first two authors equally contributed to this article.