title: RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining.
abstract: Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ 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 Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ 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 Aβ. 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 Aβ 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, Aβ 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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Hadar
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Milanesi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Squassina
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Niola
authors.affiliation: Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Chillotti
authors.affiliation: Bioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: The Genomic Analysis Laboratory, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Yaron
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Martásek
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Rehavi
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Adams Super Center for Brain Studies, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Adams Super Center for Brain Studies, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Gozes
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Adams Super Center for Brain Studies, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Gurwitz
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002460:Cell Line; D019295:Computational Biology; D057225:Data Mining; D042241:Early Diagnosis; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D058225:Plaque, Amyloid / Q000235:genetics* / Q000473:pathology; D020710:RGS Proteins / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D005819:Genetic Markers; D020710:RGS Proteins; C087182:RGS2 protein, human