title: Antisense miR-132 blockade via the AChE-R splice variant mitigates cortical inflammation.
abstract: MicroRNA (miR)-132 brain-to-body messages suppress inflammation by targeting acetylcholinesterase (AChE), but the target specificity of 3'-AChE splice variants and the signaling pathways involved remain unknown. Using surface plasmon resonance (SPR), we identified preferential miR-132 targeting of soluble AChE-R over synaptic-bound AChE-S, potentiating miR-132-mediated brain and body cholinergic suppression of pro-inflammatory cytokines. Inversely, bacterial lipopolysaccharide (LPS) reduced multiple miR-132 targets, suppressed AChE-S more than AChE-R and elevated inflammatory hallmarks. Furthermore, blockade of peripheral miR-132 by chemically protected AM132 antisense oligonucleotide elevated muscle AChE-R 10-fold over AChE-S, and cortical miRNA-sequencing demonstrated inverse brain changes by AM132 and LPS in immune-related miRs and neurotransmission and cholinergic signaling pathways. In neuromuscular junctions, AM132 co-elevated the nicotinic acetylcholine receptor and AChE, re-balancing neurotransmission and reaching mild muscle incoordination. Our findings demonstrate preferential miR-132-induced modulation of AChE-R which ignites bidirectional brain and body anti-inflammatory regulation, underscoring splice-variant miR-132 specificity as a new complexity level in inflammatory surveillance.
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Nibha
authors.initials: N
authors.lastname: Mishra
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Friedson
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Geula
authors.initials: G
authors.lastname: Hanin
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Uriya
authors.initials: U
authors.lastname: Bekenstein
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Meshi
authors.initials: M
authors.lastname: Volovich
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: David S
authors.initials: DS
authors.lastname: Greenberg
authors.affiliation: The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.|The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D007527:Isoenzymes; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism
chemical_list: D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D011978:Receptors, Nicotinic; D000110:Acetylcholinesterase