Abstract
BackgroundToll-like receptors (TLRs), as major innate immune mediators, may be involved in clearance of cerebral amyloid-β (Aβ) deposits. Recently, a novel TLR9 signaling pathway has been uncovered, which is functionally associated with the immune inflammatory response and reducing Aβ burden in Alzheimer’s disease (AD) mice. Therefore, TLR9 might represent a reasonable functional candidate gene for AD.FindingsOur study investigated 1,133 sporadic late-onset AD (LOAD) and 1,159 healthy controls matched for sex and age in a large Han Chinese population. One selected functional rs187084 polymorphism within the TLR9 gene was genotyped by polymerase chain reaction-ligase detection reaction in a case–control associated study. The TLR9 rs187084 variant homozygote GG was significantly associated with a decreased LOAD risk after adjusting for age, gender, and ApoE ϵ4 status by logistic regression analysis (P = 0.035). Our result showed significant evidence of the interaction of ApoE ϵ4 with rs187084. When we further stratified our data by the ApoE ϵ4 status, we detected significant differences in the genotype and allele distributions of rs187084 between LOAD patients and controls in ApoE ϵ4 carriers (P < 0.001, P = 0.003, respectively). Moreover, we examined TLR9 expression in peripheral blood monocytes by flow cytometry, and the GG genotype of the TLR9 rs187084 polymorphism was associated with a higher TLR9 expression than two other genotypes in LOAD patients.ConclusionOur findings support the hypothesis that the TLR9 polymorphism may modify LOAD risk in the Han Chinese population.
Highlights
Toll-like receptors (TLRs), as major innate immune mediators, may be involved in clearance of cerebral amyloid-β (Aβ) deposits
We found significantly lower Mini-Mental State Examination (MMSE) scores in late-onset AD (LOAD) patients compared to the
We evaluated single-nucleotide polymorphism (SNP) rs187084 effects under different models using logistic regression adjusting for age, gender, and Apolipoprotein E (ApoE) ε4 status
Summary
Toll-like receptors (TLRs), as major innate immune mediators, may be involved in clearance of cerebral amyloid-β (Aβ) deposits. A novel TLR9 signaling pathway has been uncovered, which is functionally associated with the immune inflammatory response and reducing Aβ burden in Alzheimer’s disease (AD) mice. The cardinal pathological hallmark of AD is amyloid-β (Aβ) deposits in neuritic plaques and cerebral vessels [2] which are closely associated with inflammatory responses such as activated microglia in brain [3]. Unlike TLR2 and TLR4, TLR9 agonism did not aggravate Aβ-induced microglial activation in the immune response [9].
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