Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease. The study of blood-based biomarkers has lasted for a long time in AD, because it supports the concept that peripheral changes are involved in AD pathology. But it is still unclear how peripheral blood is involved in the temporal characteristic molecular mechanisms of AD from aging to mild cognitive impairment (MCI) and which cells are responsible for the molecular mechanisms. The main purpose of our study is to gain a systematic and comprehensive understanding of temporal characteristic networks of peripheral blood in AD using whole blood samples with 329 case-control samples, including 104 normal elderly control subjects (CTL), 80 MCI who are susceptible to AD, and 145 AD, by the weighted gene co-expression network analysis (WGCNA). The module-trait relationships were constructed and module preservation was validated with independent datasets GSE63061, GSE97760, GSE18309, GSE29378, GSE28146, and GSE29652. Our results indicate that the down-regulated protein modification and ubiquitin degradation systems, and the up-regulated insulin resistance both play a major role in MCI, while the up-regulated inflammatory cascade dominates in AD, which is mainly mediated by monocytes, macrophages. Although there is mixed activation of M1 and M2 macrophages in all stages of AD, the immune neutral state or M2 polarization may predominate in MCI, and M1 polarization may predominate in AD. Moreover, we found that TRPV2, NDUFV1, ATF4, HSPA8, STAT3 and LUC7L3 may mediate the pathological changes in MCI, while SIRPA, LAMP-2, NDUFB5, HSPA8, STAT3 and FPR2 may mediate the conversion from MCI-AD or the pathological changes in AD, which provide a basis for the treatment based on the peripheral blood system. In addition, we also found that the combined diagnosis based on a panel of genes from the red, blue, and brown modules have a moderate diagnostic effect on distinguishing MCI and AD from CTL, suggesting that those panels of genes may be used for detection of MCI and prediction of this conversion from MCI to AD. Our research emphasizes that pathological changes, based on temporal characteristics of peripheral blood, provide a theoretical basis for targeted peripheral treatment based on appropriate times and identified several diagnostic markers.
Highlights
Alzheimer’s disease (AD), the most common type of dementia, affects more than 50 million people worldwide (Hodson, 2018)
Modules associated with mild cognitive impairment (MCI) were the yellow, turquoise, and black modules, which are mainly enriched in monocytes, macrophages, Th1 cells, and microglia, mediating the down-regulation of metabolic and catabolic process, ubiquitin-mediated proteolysis, and NF-kappa B signaling pathway, as well as the up-regulation of RNA processing, ribonucleoprotein complex biogenesis, and RNA transport, et al speaking, the yellow and turquoise modules with moderate-high preservation in validation datasets suggest that RNA metabolism and inflammatory signaling pathway were down-regulated in both microglia and peripheral blood monocytes and macrophages, while ubiquitin-mediated proteolysis and protein modification process were down-regulated in peripheral blood monocytes and macrophages
The black module with high preservation in peripheral whole blood or monocyte datasets indicates that ribonucleoprotein complex biogenesis and RNA processing were up-regulated in regulatory T cells and Th1 cells
Summary
Alzheimer’s disease (AD), the most common type of dementia, affects more than 50 million people worldwide (Hodson, 2018). The amyloid cascade hypothesis still dominates the etiology of AD, which reveals the temporal characteristics of AD brain pathological changes: that β-amyloid (Aβ) deposition occurs early, followed by changes in brain function and metabolism, and alterations in biomarkers of neurodegeneration, such as tau-mediated neuronal injury and structural changes, eventually lead to cognitive impairment (Mattsson et al, 2009; Jack et al, 2010; García-Ribas et al, 2014). AD is divided into three different stages: asymptomatic or pre-clinical stage, mild cognitive impairment (MCI), and AD stage (Dubois et al, 2010; Gold and El Khoury, 2015). It is universally accepted that AD has a long preclinical or asymptomatic stage, which starts approximately 15–20 years before the onset of clinical symptoms (Sperling et al, 2011). Early diagnosis and treatment are important for delaying the progression of AD
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