Alzheimer's disease; acetylcholinesterase (AChE); genetics; neuroinflammation; single nucleotide polymorphisms (SNPs); Cholinesterase Inhibitors; MicroRNAs; Acetylcholinesterase; Acetylcholine; Acetylcholine/metabolism; Acetylcholinesterase/metabolism; Animals; Cholinesterase Inhibitors/pharmacology; Homeostasis/drug effects; Humans; MicroRNAs/drug effects; MicroRNAs/genetics; Polymorphism, Single Nucleotide/drug effects; Polymorphism, Single Nucleotide/genetics; Homeostasis; Polymorphism, Single Nucleotide; Biochemistry; Cellular and Molecular Neuroscience
Résumé :
[en] Acetylcholine signaling is essential for cognitive functioning and blocks inflammation. To maintain homeostasis, cholinergic signaling is subjected to multi-leveled and bidirectional regulation by both proteins and non-coding microRNAs ('CholinomiRs'). CholinomiRs coordinate the cognitive and inflammatory aspects of cholinergic signaling by targeting major cholinergic transcripts including the acetylcholine hydrolyzing enzyme acetylcholinesterase (AChE). Notably, AChE inhibitors are the only currently approved line of treatment for Alzheimer's disease patients. Since cholinergic signaling blocks neuroinflammation which is inherent to Alzheimer's disease, genomic changes modifying AChE's properties and its susceptibility to inhibitors and/or to CholinomiRs regulation may affect the levels and properties of inflammasome components such as NLRP3. This calls for genomic-based medicine approaches based on genotyping of both coding and non-coding single nucleotide polymorphisms (SNPs) in the genes involved in cholinergic signaling. An example is a SNP in a recognition element for the primate-specific microRNA-608 within the 3' untranslated region of the AChE transcript. Carriers of the minor allele of that SNP present massively elevated brain AChE levels, increased trait anxiety and inflammation, accompanied by perturbed CholinomiR-608 regulatory networks and elevated prefrontal activity under exposure to stressful insults. Several additional SNPs in the AChE and other cholinergic genes await further studies, and might likewise involve different CholinomiRs and pathways including those modulating the initiation and progression of neurodegenerative diseases. CholinomiRs regulation of the cholinergic system thus merits in-depth interrogation and is likely to lead to personalized medicine approaches for achieving better homeostasis in health and disease. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Disciplines :
Neurologie
Auteur, co-auteur :
Simchovitz, Alon; Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel
HENEKA, Michael ; Department of Neurology, University Bonn, Bonn, Germany
Soreq, Hermona; Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Personalized genetics of the cholinergic blockade of neuroinflammation.
Israel Science Foundation Ministry of Science and Technology, Israel Deutsche Forschungsgemeinschaft Seventh Framework Programme
Subventionnement (détails) :
Work performed by A.S and H.S was supported by The Israel Science Foundation (Grant No. 817/13) and the Israeli Ministry of Science and Technology Grant Number 53140. MTH was supported by a grant from the German Research Council (DFG KFO177, TP8) and by the EU's Seventh Framework Programme InMIND. Michael Heneka is an editor with the Journal of Neurochemistry.Other than that, the authors declare they have no conflict of interests.
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