Role of TRPM2 channels and ADPR signalling in mediating the synaptotoxic effects of Aβ oligomers

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dc.contributor.authorMyhalatyuk, Olha
dc.contributor.examiningcommitteeWright, Galen (Pharmacology and Therapeutics)en_US
dc.contributor.examiningcommitteeStobart, Jill (Pharmacy)en_US
dc.contributor.supervisorKauppinen, Tiina
dc.contributor.supervisorJackson, Michael
dc.date.accessioned2022-11-14T21:11:55Z
dc.date.available2022-11-14T21:11:55Z
dc.date.copyright2022-11-10
dc.date.issued2022-11-09
dc.date.submitted2022-11-10T17:34:46Zen_US
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by memory loss and cognitive decline due to accumulation of amyloid-beta oligomers (AβOs). AβOs are known to disrupt synaptic transmission and plasticity in the form of long-term potentiation (LTP). AβOs also trigger chronic microglial pro-inflammatory responses that contribute to impaired synaptic transmission and plasticity. Our past work shows that microglial NMDA receptors are coupled to a signalling cascade, which involves activation of PARP-1, previously recognized, as a central signalling hub that drives inflammation through NF-κB. Moreover, our recent work suggests that sustained microglial PARP-1 activation requires Ca2+ influx initiated as a result of transient receptor potential melastatin-2 channel (TRPM2) activation, a Ca2+ permeable channel most highly expressed in microglia. A by-product of PARP-1 activation, ADP-ribose is required for TRPM2 activation. Thus, NMDAR/PARP-1/TRPM2/ADPR activity is coupled through positive feedback. Our unpublished findings suggest PARP-1 to be crucial in mediating the synaptotoxic effects of AβOs on synaptic plasticity. In my study I aim to establish the role of microglial NMDARs, TRPM2 and ADPR signalling on synaptic plasticity and whether pharmacological inhibition can prevent the synaptotoxic effects of AβOs on LTP. Acute hippocampal slices were treated with AβO, TRPM2 and NUDT5 inhibitors using field electrophysiology to assess synaptic plasticity. Using microglia specific NR1-iKO mice as well as pharmacological inhibitors for TRPM2 and NUDT5, an enzyme linked to ADPR metabolism, we evaluated the contribution of microglial NMDARs/TRPM2/ADPR signalling of AβO effect on synaptic plasticity. Our findings, demonstrate that 1) synaptotoxic effects of AβOs are mediated through TRPM2 channels and ADPR signalling and 2) microglial NMDA receptors may be responsible for initiating the TRPM2/ADPR mediated signalling axis. To conclude, TRPM2/ADPR signalling axis has been shown to be important in mediating the synaptotoxic effects of AβOs on synaptic plasticity. Pharmacological inhibition of TRPM2 with two structurally different agents was effective in both sexes. Thus, TRPM2 channels could potentially make a promising target for the development of therapeutic agents for the effective treatment of AD.en_US
dc.description.noteFebruary 2023en_US
dc.description.sponsorshipResearch Manitoba Alzheimer Societyen_US
dc.identifier.urihttp://hdl.handle.net/1993/36970
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectmicrogliaen_US
dc.subjectneuroscienceen_US
dc.subjectinflammationen_US
dc.subjectPARP-1en_US
dc.subjectAβ oligomersen_US
dc.subjectTRPM2en_US
dc.subjectLTPen_US
dc.subjectsynaptic plasticityen_US
dc.subjectneuroinflammationen_US
dc.titleRole of TRPM2 channels and ADPR signalling in mediating the synaptotoxic effects of Aβ oligomersen_US
dc.typemaster thesisen_US
local.subject.manitobanoen_US
oaire.awardNumberpjt-173550en_US
oaire.awardTitleInterplay of neuroinflammation and synaptic plasticity in neurodegerationen_US
oaire.awardURIhttps://webapps.cihr-irsc.gc.ca/cris/detail_e?pResearchId=9815505&p_version=CRIS&p_language=E&p_session_id=1333597en_US
project.funder.identifierhttps://doi.org/10.13039/501100000024en_US
project.funder.nameCanadian Institutes of Health Researchen_US
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