Background: Late-onset Alzheimer’s disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study invloved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ, TNF-α, IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ, TNF-α, and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction.

Serotonin or 5-hydroxytryptamine (5-HT) is primarily involved in the regulation of learning and memory. Pathological changes in metabolism or functional imbalance of 5-HT has been associated with Alzheimer's disease (AD). The hypothesis tested is that in peripheral blood, markers of the serotonergic pathway can be used as a diagnostic tool for AD. The current study measured the relative expression of 5-HT receptors (5-HTR2A and 5-HTR3A) as well as the 5-HT catalytic enzyme, Monoamine oxidase A (MAO-A) mRNA in Peripheral Blood Mononuclear Cells (PBMCs) of patients with late-onset Alzheimer's disease (LOAD) and age-matched controls. 5-HTR2A, 5-HTR3A, and MAO-A mRNA expressions were examined in PBMCs of 30 patients with LOAD and 30 control individuals. Real-time quantitative PCR was used to measure mRNA expression. The dementia status of patients in this study was assessed using a Mini-Mental State Examination (MMSE). Mean data of relative mRNA expression of 5-HTR2A, 5-HTR3A and MAO-A were significantly lower in PBMCs of patients with LOAD compared with controls. Based on the down-regulation of serotonergic markers in PBMCs, our findings may be another claim to the systemic nature of LOAD. The role of peripheral serotonergic downregulation, in the pathogenesis of AD, needs to be further studied. Given the extremely convenient access to PBMCs, these molecular events may represent more complete dimensions of AD neuropathophysiology or possibly lead to a new direction in studies focused on blood-based markers.