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Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti

Bimodal modulation of alpha5 GABAA receptors in an experimental model of Alzheimer’s disease

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2022
Disertacija_13535.pdf (2.087Mb)
Authors
Aranđelović, Jovana
Contributors
Savić, Miroslav
Batinić, Bojan
Todorović, Lidija
Trbović, Aleksandar
Doctoral thesis (Published version)
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Abstract
Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu,objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju,ekspresiju subjedinica GABAA receptora i neuroinflamaciju.Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgen...ih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki.U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom.

Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotional...ityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.

Keywords:
modulacija α5 GABAA receptora / 5xFAD / kognicija / euroinflamacija / Alchajmerova bolest / α5 GABAA receptor modulation / cognition / neuroinflammation / Alzheimer’s disease
Source:
Универзитет у Београду, 2022
Publisher:
  • Универзитет у Београду, Фармацеутски факултет
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_21433
URI
https://eteze.bg.ac.rs/application/showtheses?thesesId=9095
https://fedorabg.bg.ac.rs/fedora/get/o:29380/bdef:Content/download
https://plus.cobiss.net/cobiss/sr/sr/bib/77009673
https://nardus.mpn.gov.rs/handle/123456789/21433
https://farfar.pharmacy.bg.ac.rs/handle/123456789/4968
Collections
  • Doktorati
Institution/Community
Pharmacy
TY  - THES
AU  - Aranđelović, Jovana
PY  - 2022
UR  - https://eteze.bg.ac.rs/application/showtheses?thesesId=9095
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:29380/bdef:Content/download
UR  - https://plus.cobiss.net/cobiss/sr/sr/bib/77009673
UR  - https://nardus.mpn.gov.rs/handle/123456789/21433
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4968
AB  - Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu,objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju,ekspresiju subjedinica GABAA receptora i neuroinflamaciju.Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki.U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom.
AB  - Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotionalityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.
PB  - Универзитет у Београду, Фармацеутски факултет
T2  - Универзитет у Београду
T1  - Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti
UR  - https://hdl.handle.net/21.15107/rcub_nardus_21433
ER  - 
@phdthesis{
author = "Aranđelović, Jovana",
year = "2022",
abstract = "Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu,objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju,ekspresiju subjedinica GABAA receptora i neuroinflamaciju.Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki.U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom., Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotionalityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti",
url = "https://hdl.handle.net/21.15107/rcub_nardus_21433"
}
Aranđelović, J.. (2022). Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti. in Универзитет у Београду
Универзитет у Београду, Фармацеутски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_21433
Aranđelović J. Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti. in Универзитет у Београду. 2022;.
https://hdl.handle.net/21.15107/rcub_nardus_21433 .
Aranđelović, Jovana, "Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti" in Универзитет у Београду (2022),
https://hdl.handle.net/21.15107/rcub_nardus_21433 .

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