Dysregulation of metabotropic glutamate mGlu3 receptor in aging and Alzheimer’s disease. Role of alternative splicing isoforms.

SÁEZ ALBANY; TURATI, JUAN; MARÍA JULIETA RUDI; BEAUQUIS JUAN; CARNIGLIA LILA; LÓPEZ COUSELO FEDERICO; SABA JULIETA; CARUSO CARLA; SARAVIA FLAVIA; LASAGA MERCEDES; DURAND DANIELA

Simposio; Simposio Latbrain Estado actual y retos de las investigaciones en enfermedades neurodegenerativas y epilepsia en Latinoamérica; 2022

Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that astroglial mGlu3R activation protects hippocampal neurons from Aβ neurotoxicity through stimulation of both neurotrophin release and Aβ uptake.Alternative-spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. However, its role in neurodegeneration has been overlooked. We described for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer’s disease (AD) in the preclinical murine model PDAPP-J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. mGlu3Δ4 levels were drastically increased during aging in nontransgenic mice, but prematurely over-expressed in 5-month-old PDAPP-J20-derived hippocampi, prior to massive senile plaque deposition. On the other hand, hippocampal mGlu3R levels progressively decreased with age in PDAPP-J20 mice but increased at 9 month-old in nontransgenic mice, which was also observed at the glial level after isolation by Percoll gradients. Also, we found that mGlu3Δ4 co-precipitated with mGlu3R in PDAPP-J20 mice. We further showed that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aβ, thereby discouraging a causal effect of Aβ on mGlu3Δ4 induction. On the other hand, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R-dependent Aβ glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron–glia co-cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R-mediated glial neuroprotective pathways, which may lie behind AD onset. mGlu3R could be detected in human serum by western blot, which gives the chance to measure mGlu3/mGlu3Δ4 levels as novel AD biomarkers.