Jiajia Wang

Characteristic Transformation of Blood Transcriptome in Alzheimer's Disease

Blood transcriptome has emerged as a potential resource for the discovery of biomarkers for Alzheimers disease (AD). However, the validity of blood transcriptome in the early diagnosis of AD has yet to be extensively tested. In this work, we analyzed published data on AD blood transcriptome and revealed the characteristic perturbation of cellular functional units, including upregulation of environmental responses (immune response, survival/death signaling, and cellular recycling) and down-regulation of core metabolism (energy metabolism and translation/splicing). This characteristic perturbation was unique to AD based on the comparison with blood transcriptome from other neurological disorders and complex diseases. More importantly, similar perturbation was observed in both AD and mild cognitive impairment (MCI) groups. This perturbation pattern was further validated in our independent microarray experiment in a small Chinese cohort. In addition, the potential effect of aging and lifestyle on blood transcriptome was discussed. Based on the analyses, we propose that the transformation of the blood transcriptome in AD is an integrated part of the disease mechanism and has potential to serve as a reliable biomarker for assisting the early diagnosis as well as monitoring purpose. Therefore, more independent studies on blood transcriptome of AD and MCI with larger sample size are warranted.

Genomics in Neurological Disorders

Neurological disorders comprise a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center (i.e., the brain) in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be discussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer’s disease and autism spectrum disorder.

AlzBase: an Integrative Database for Gene Dysregulation in Alzheimer's Disease.

Alzheimer’s disease (AD) affects a significant portion of elderly people worldwide. Although the amyloid-β (Aβ) cascade hypothesis has been the prevailing theory for the molecular mechanism of AD in the past few decades, treatment strategies targeting the Aβ cascade have not demonstrated effectiveness as yet. Thus, elucidating the spatial and temporal evolution of the molecular pathways in AD remains to be a daunting task. To facilitate novel discoveries in this filed, here, we have integrated information from multiple sources for the better understanding of gene functions in AD pathogenesis. Several categories of information have been collected, including (1) gene dysregulation in AD and closely related processes/diseases such as aging and neurological disorders, (2) correlation of gene dysregulation with AD severity, (3) a wealth of annotations on the functional and regulatory information, and (4) network connections for gene-gene relationship. In addition, we have also provided a comprehensive summary for the top ranked genes in AlzBase. By evaluating the information curated in AlzBase, researchers can prioritize genes from their own research and generate novel hypothesis regarding the molecular mechanism of AD. To demonstrate the utility of AlzBase, we examined the genes from the genetic studies of AD. It revealed links between the upstream genetic variations and downstream endo-phenotype and suggested several genes with higher priority. This integrative database is freely available on the web at http://alz.big.ac.cn/alzBase.

Distinctive RNA expression profiles in blood associated with Alzheimer disease after accounting for white matter hyperintensities.

Background:Defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH. Methods:RNA from whole blood was processed on whole-genome microarrays. Results:A total of 293 probe sets were differentially expressed in AD versus controls, 5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies. Regulated blood genes included MMP9, MME (Neprilysin), TGF&bgr;1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2. Conclusions:RNA expression is altered in AD blood irrespective of WMH status. Some genes are shared with AD brain.

Perturbation of the transcriptome: implications of the innate immune system in Alzheimer's disease.

Alzheimers disease (AD) is a neurodegenerative disease with broad impact. Although Aβ and tau have been proposed as the key molecules in the disease mechanism, comprehensive understanding of AD pathogenesis requires a systemic view at the genomic level. From studies on the brain transcriptome of AD, we have gradually realized the contribution of the immune system to AD development. Recent explorations on the blood transcriptome of AD patients have revealed robust immune activation in the peripheral blood. The combination of transcriptome studies and other types of studies has further elucidated the roles of specific immune pathways in distinct cell types during AD development and highlighted the critical contributions from immune genes such as TREM2.

Common Aging Signature in the Peripheral Blood of Vascular Dementia and Alzheimer’s Disease

Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most dominant forms of dementia in elderly people. Due to the large overlap between AD and VaD in clinical observations, great controversies exist regarding the distinction and connection between these two types of senile dementia. Here for the first time, we resort to the gene expression pattern of the peripheral blood to compare AD and VaD objectively. In our previous work, we have demonstrated that the dysregulation of gene expression in AD is unique among the examined diseases including neurological diseases, cancer, and metabolic diseases. In this study, we found that the dysregulation of gene expression in AD and VaD is quite similar to each other at both functional and gene levels. Interestingly, the dysregulation started at the early stages of the diseases, namely mild cognitive impairment (MCI) and vascular cognitive impairment (VCI). We have also shown that this signature is distinctive from that of peripheral vascular diseases. Comparison with aging studies revealed that the most profound change in AD and VaD, namely ribosome, is consistent with the accelerated aging scenario. This study may have implications to the common mechanism between AD and VaD.

Chromosome 19p in Alzheimer's disease: when genome meets transcriptome.

Genetic studies have identified several genomic loci including chr19p13.2 relevant to Alzheimers disease (AD) susceptibility. However, the functional roles of these genomic loci in AD pathogenesis require further clarification. Transcriptome as an endophenotype is critical for the understanding of disease mechanism. Here we demonstrate that chr19p is the most significantly perturbed chromosome region in AD brain transcriptome. With dual evidence from genome and transcriptome, chr19p likely play a special role in AD pathogenesis.

Alzheimer's Disease: Genomics and Beyond.

Alzheimers disease (AD) is a major form of senile dementia. Despite the critical roles of Aβ and tau in AD pathology, drugs targeting Aβ or tau have so far reached limited success. The advent of genomic technologies has made it possible to gain a more complete picture regarding the molecular network underlying the disease progression which may lead to discoveries of novel treatment targets. In this review, we will discuss recent progresses in AD research focusing on genome, transcriptome, epigenome, and related subjects. Advancements have been made in the finding of novel genetic risk factors, new hypothesis for disease mechanism, candidate biomarkers for early diagnosis, and potential drug targets. As an integration effort, we have curated relevant data in a database named AlzBase.

Web Resources for Stem Cell Research

In this short review, we have presented a brief overview on major web resources relevant to stem cell research. To facilitate more efficient use of these resources, we have provided a preliminary rating based on our own user experience of the overall quality for each resource. We plan to update the information on an annual basis.