4.7 Article

RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining

Journal

TRANSLATIONAL PSYCHIATRY
Volume 6, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/tp.2016.179

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Funding

  1. Israel Science Foundation [1424/14]
  2. AMN Foundation
  3. Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology
  4. Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University
  5. Yoran Institute for Human Genome Research at Tel Aviv University
  6. Shabbetai Donnolo Fellowships between Italy and Israel
  7. Charles University in Prague [P24/LF1/3, UNCE 204011/2012]
  8. MZ CR [RVO-VFN 64165/2012]
  9. I-CORE Program of the Planning and Budgeting Committee, Israel

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Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-beta (A beta) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of A beta in AD pathology have been raised as A beta is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to A beta neurotoxicity and hence more likely to develop AD when aging brains start accumulating A beta plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to A beta. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P = 0.0085) in LCLs from healthy individuals exhibiting high vs low A beta sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P = 0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, A beta sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

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