Role of the Transforming-Growth-Factor-β1 Gene in Late-Onset Alzheimer’s Disease: Implications for the Treatment

Abstract

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. LOAD has a complex and largely unknown etiology with strong genetic determinants. Genetics of LOAD is known to involve several genetic risk factors among which the Apolipoprotein E (APOE) gene seems to be the major recognized genetic determinant. Recent efforts have been made to identify other genetic factors involved in the pathophysiology of LOAD such as genes associated with a deficit of neurotrophic factors in the AD brain. Genetic variations of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), and transforming-growth-factor-β1 (TGF-β1) are known to increase the risk to develop LOAD and have also been related to depression susceptibility in LOAD. Transforming-Growth-Factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against ß-amyloid-induced neurodegeneration. Recent evidence suggests that a specific impairment in the signaling of TGF-β is an early event in the pathogenesis of AD. TGF-β1 protein levels are predominantly under genetic control, and the TGF-β1 gene, located on chromosome 19q13.1–3, con-tains several single nucleotide polymorphisms (SNPs) upstream and in the transcript region, such as the SNP at codon +10 (T/C) and +25 (G/C), which is known to influence the level of expression of TGF-β1. In the present review, we summarize the current literature on genetic risk factors for LOAD, focusing on the role of the TGF-β1 gene, finally discussing the possible implications of these genetic studies for the selection of patients eligible for neuroprotective strategies in AD.

Identification and association of relationships between selected personal and environmental factors and formal components of temperament and strategies of coping with stress in asthmatic patients

“…An increase in cytokine expression led to a decreased tendency of a rapid reaction to stimuli (morbid, stressful, emotional). Numerous studies allow one to claim that signal pathways of TGFβ1 and BDNF, mediated by SMAD proteins in the induction of disturbances of sensitivity, emotional resistance and mood (mainly depression) in the course of chronic inflammatory diseases play here a great role [60,64,65,66,67]. Thus, in the study the authors emphasized the role and importance of selected molecular markers (SNP Tth111I of NR3C1 gen and TGFβ1 expression).…”

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer’s Disease Risk

“…LOAD form accounts for more than 90% of AD cases [30]. To date, the APOE gene is the major genetic factor in LOAD susceptibility [31], while other genetic factors related with LOAD susceptibility remain largely unknown.…”

Arg25Pro (c.915G>C) polymorphism of transforming growth factor β1 gene suggests an association with increased risk for Hashimoto's thyroiditis

“…Signal sequence regulates posttranslational protein synthesis which finally affects the level of expression, secretion of this cytokine results in low or high TGFβ1 plasma levels [14]. It has been demonstrated that the transition at codon 25 of GNC (ArgNPro substitution) reduces the secretion and plasma levels of TGFβ1 [32,33].…”

“…and the Leu (T) allele [32,33], whereas others related it to the Pro (C) allele [15]. Changes at both codon 10 and 25 result in an alteration to the hydrophobic α-helix of the signal peptide sequence, thereby reducing its ability to direct protein transport across the endoplasmic reticulum [14,34].…”

“…The TGFβ1 gene, located on chromosome 19q13.1-3, contains seven exons that give rise to a precursor protein of 390 amino acids [13], and more than 10 polymorphic loci are presently known [14]. The hotspots focus on the single nucleotide polymorphisms (SNPs) at codon 10 and 25, which change the amino acid sequence of the signal peptide, and were known to influence the level of expression of TGFβ1 [14]. The polymorphisms at codons 10 and 25 (positions +869 and +915 of TGFβ1 gene) result in a Leu to Pro, and Arg to Pro change, respectively.…”