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

Song, Fuhai; Qian, Ying; Xing, Peng; Han, Guangchun; Wang, Jiajia; Bai, Zhouxian; Crack, Peter J; Lei, Hongxing

doi:10.1016/j.coph.2015.09.015

Cited by 15 publications

(19 citation statements)

References 55 publications

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“…Evidence of CSF sTREM2 positively correlating with glial protein YKL-40 in CSF [ 314 , 316 ], another proposed AD immune biomarker, in addition to immunosuppressive agents causing a reduction in CSF sTREM2 levels [ 313 ] are consistent with this theory. Changes in sTREM2 appear to be independent of ApoE4 status [ 318 – 320 ]. Further work assessing how sTREM2 generation changes with microglial phenotype will be needed to definitively validate sTREM2 as an indicator of microglial activation.…”

Section: The Clinical Relevance Of Trem2mentioning

confidence: 99%

“…Moreover, Heslegrave and colleagues [ 314 ] acknowledged that sTREM2 levels in AD patients and controls, while significantly different, substantially overlap, thereby further limiting its diagnostic utility. Transcriptome-based studies found dysregulation of several innate immune genes in blood from AD patients [ 320 ], which led others to assess whether TREM2 expression might also be changed in blood. While studies did find a correlation between TREM2 expression on blood monocytes and an AD diagnosis [ 128 ], sTREM2 in plasma was shown to not correlate with CSF sTREM2 levels [ 86 ] and plasma samples yielded non-significant differences in sTREM2 of AD and FTD patients compared to healthy controls [ 86 , 225 ].…”

Section: The Clinical Relevance Of Trem2mentioning

confidence: 99%

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TREM2 in Neurodegenerative Diseases

Jay

Saucken

Landreth

2017

Mol Neurodegeneration

306

283

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TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.

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Section: The Clinical Relevance Of Trem2mentioning

confidence: 99%

Section: The Clinical Relevance Of Trem2mentioning

confidence: 99%

TREM2 in Neurodegenerative Diseases

Jay

Saucken

Landreth

2017

Mol Neurodegeneration

306

283

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“…To enhance the reproducibility of biomarker, we could also select genes consistently dys-regulated in multiple independent studies on different diseases, which further reduce the likelihood that the observed gene dys-regulation is due to population heterogeneity or transient fluctuation. We hypothesized that similar immune response may be induced in peripheral blood in different infectious and autoimmune diseases, or even in other diseases such as cancer and neurological disorders[ 9 – 11 ]. This similar immune response will be reflected on the dys-regulation of certain critical genes for immune response in blood cells.…”

Section: Introductionmentioning

confidence: 99%

The frontline of immune response in peripheral blood

et al. 2017

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Peripheral blood is an attractive source for the discovery of disease biomarkers. Gene expression profiling of whole blood or its components has been widely conducted for various diseases. However, due to population heterogeneity and the dynamic nature of gene expression, certain biomarkers discovered from blood transcriptome studies could not be replicated in independent studies. In the meantime, it’s also important to know whether a reliable biomarker is shared by several diseases or specific to certain health conditions. We hypothesized that common mechanism of immune response in blood may be shared by different diseases. Under this hypothesis, we surveyed publicly available transcriptome data on infectious and autoimmune diseases derived from peripheral blood. We examined to which extent common gene dys-regulation existed in different diseases. We also investigated whether the commonly dys-regulated genes could serve as reliable biomarkers. First, we found that a limited number of genes are frequently dys-regulated in infectious and autoimmune diseases, from which we selected 10 genes co-dysregulated in viral infections and another set of 10 genes co-dysregulated in bacterial infections. In addition to its ability to distinguish viral infections from bacterial infections, these 20 genes could assist in disease classification and monitoring of treatment effect for several infectious and autoimmune diseases. In some cases, a single gene is sufficient to serve this purpose. It was interesting that dys-regulation of these 20 genes were also observed in other types of diseases including cancer and stroke where certain genes could also serve as biomarkers for diagnosis or prognosis. Furthermore, we demonstrated that this set of 20 genes could also be used in continuous monitoring of personal health. The rich information from these commonly dys-regulated genes may find its wide application in clinical practice and personal healthcare. More validation studies and in-depth investigations are warranted in the future.

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“…AD brain and blood transcriptome studies suggest that elevated level of the innate immune system may be a suitable target for further drug development [92]. For example, glucogon-like peptide 1 analogs, the widely-studied neuro-protective agent, are involved in reducing neural inflammation among many other protective functions [93].…”

Section: Stage-specific Intervention Strategy For Admentioning

confidence: 99%

Towards Personalized Intervention for Alzheimer’s Disease

Xing

et al. 2016

Genomics, Proteomics &Amp; Bioinformatics

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Alzheimer’s disease (AD) remains to be a grand challenge for the international community despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells (iPSCs). Comprehensive information collection, better understanding of the disease mechanisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.

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

Cited by 15 publications

References 55 publications

TREM2 in Neurodegenerative Diseases

TREM2 in Neurodegenerative Diseases

The frontline of immune response in peripheral blood

Towards Personalized Intervention for Alzheimer’s Disease

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