Is mGlu3∆4R, the truncated isoform of metabotropic glutamate mGlu3 receptor, implicated in Alzheimer?s pathogenesis?

JUAN TURATI; LILA CARNIGLIA; DANIELA DURAND; TOMAS ÁLVAREZ LLENA; MERCEDES LASAGA; JULIETA RUDI; CARLA CARUSO

Buenos Aires

Congreso; SAN2020; 2020

mGlu3R exert crucial protective functions in normal and ill brain. It has been shown that human brain also expresses mGlu3∆4R, a truncated isoform of mGlu3R lacking the exon 4 coding for the transmembrane domain. In heterologous expression systems mGlu3∆4R was shown to act as a negative dominant of mGlu3R, and a possible association with schizophrenia was reported. However, the function of this isoform in CNS resident cells or in other pathologies has been largely ignored. We described for the first time a possible correlation between ∆4 and AD onset using PDAPP-J20 mice. Now, we are reporting that ∆4 is expressed by normal astrocytes and neurons and that Aβ did not induce GRM3 splicing in these cells; rather, Aβ inhibited both mGlu3R and mGlu3∆4R protein expression. Thus, we wondered if, inversely, ∆4 may lead to Aβ overproduction, considering that canonical mGlu3R regulates amyloidogenesis in astrocytes. We transfected cultured astrocytes with pCMV-GRM3∆4 plasmid and observed increased levels of ∆4 mRNA and a disorganization of astrocyte monolayer, accompanied by increased cell death compared to mock cells. Indeed, ∆4 overexpression reduced Scavenger receptor-A mRNA levels, suggesting a failure in Aβ clearance. A possible reduction in mGlu3R protein levels after ∆4 overexpression was also observed in preliminary results. Taken together, our results encourage us to study mGlu3∆4R as a novel target in AD research field, possibly becoming an early biomarker of AD.