A Decline in Metabotropic Glutamate <scp>mGlu3</scp> Receptor Levels Is Associated With Amyloid Plaques in Alzheimer's Disease and Is Detectable in Serum During Mild Cognitive Impairment

Subtype 3 metabotropic glutamate receptors (mGlu3R) play neuroprotective roles and are involved in superior executive functions and memory in humans. However, this target has been scarcely studied in the context of Alzheimer's disease (AD). Our previous results showed that astroglial mGlu3R promoted the non-amyloidogenic cleavage of amyloid precursor protein and triggered amyloid-β (Aβ) clearance by astrocytes. Remarkably, mGlu3R is downregulated in hippocampi from aged PDAPP-J20 mice, whereas the truncated isoform of the receptor, mGlu3Δ4, is early accumulated. Indeed, mGlu3Δ4 inhibited mGlu3R protective function in astrocytes. In the present paper, we aimed to investigate mGlu3Δ4/mGlu3R expression in AD brains and to assess whether changes in these proteins can be detected in human biofluids during mild cognitive impairment (MCI). Bioinformatics analysis of transcriptomic data from human brains indicated that mGlu3R expression was reduced in amyloid plaque-associated areas and in AD astrocytes. At the protein level, mGlu3R immunostaining was lower within the plaque niche in hippocampal slices from PDAPP-J20 mice, whereas cultured glial cells from these mice expressed lower mGlu3R than non-transgenic mice as early as 2 months-old of age. Furthermore, mGlu3R protein levels determined by western blot inversely correlated with histopathology in human AD hippocampi. Interestingly, mGlu3R (but not mGlu3Δ4) protein was detectable by western blot in serum samples from MCI and control subjects. We showed that mGlu3R levels were significantly reduced in MCI serum compared to those of cognitively intact individuals. Moreover, its levels positively correlated with serum Aβ. Our results showed changes in mGlu3R expression in AD brains that might reflect early glial receptor dysfunction, whereas reduced serum mGlu3R levels may be associated with mild cognitive impairment that precedes AD.