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.
Highlights
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most frequent cause of dementia
Lower RGS2 expression levels were 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
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
Summary
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most frequent cause of dementia. Old age is a major AD risk factor: the annual AD incidence increases from 1% between ages of 60 and 70 years to 6–8% at the age of 85 or older.[1,2] AD is characterized by misfolded protein pathological brain hallmarks: extracellular deposits of amyloid-β (Aβ) plaques and accumulation of phosphorylated tau neurofibrillary tangles. The Aβ1–42 peptide aggregates are predominant in AD brain plaques and considered the most neurotoxic Aβ form.[3,4,5,6,7] there are individuals who exhibit Aβ plaques in the absence of dementia symptoms.[1,8,9,10] Mild cognitive impairment (MCI) is a state when there is mild loss of memory, considered normal for old age. Fifty percent of MCI patients will progress to AD over 4 years.[1]
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