Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti
Bimodal modulation of alpha5 GABAA receptors in an experimental model of Alzheimer’s disease
Doktorand
Aranđelović, JovanaMentor
Savić, Miroslav M.Članovi komisije
Batinić, BojanTodorović, Lidija
Trbović, Aleksandar
Metapodaci
Prikaz svih podataka o disertacijiSažetak
Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne procese
značajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFAD
modelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5
GABAA 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 i
netransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresije
gena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusu
i prefrontalnom korteksu pomoću qPCR metode.
Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalno
prepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenih
mužjaka. NAM tretman je smanjio socijalnu interakciju ...kod transgenih i netransgenih
mužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat na
kognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratila
na 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 povećao
Gabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivne
simptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornih
gena kod transgenih ženki i astroglioze kod transgenih mužjaka.
Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efekte
kod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva više
studija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima sa
izraženom neuroinflamacijom.
Aims: GABAergic modulation involved in cognitive processing appears to be substantially
changed in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed to
assess if negative and positive allosteric modulators of α5 GABAA receptors (NAM and
PAM, respectively) would affect social interaction, social, object and spatial memory,
sensorimotor function, emotionality, motivation, expression of GABAA receptor subunits
and neuroinflammation.
Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenic
and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene
expressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determined
in hippocampus and prefrontal cortex by qPCR analysis.
Results: PAM treatment impaired spatial learning in transgenic females, and social
recognition and motor function in both transgenic and non-transgenic males and in
transgenic males, respectively. NAM treatment declined social interaction a...nd emotionality
in both transgenic and non-transgenic males and transgenic males, respectively. NAM had a
beneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, both
treatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. In
prefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2
in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,
while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions
in transgenic females and astrogliosis in transgenic males.
Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects in
transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more
studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with
prominent neuroinflammation.