Role of TRPM2 channels and ADPR signalling in mediating the synaptotoxic effects of Aβ oligomers
Alzheimer’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 Our unpublished findings suggest PARP-1 to be crucial in mediating the synaptotoxic effects of AβOs on synaptic plasticity.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.