Astroglial metabotropic glutamate receptor 3 induces the non-amyloidogenic pathway by modulating alpha- and beta- secretase expression.

DURAND DANIELA; CARNIGLIA LILA; CARUSO CARLA; LASAGA MERCEDES

New Orleans

Congreso; Society for Neuroscience 42nd Annual Meeting; 2012

Society for Neurosciences

Alzheimer’s disease is characterized by the presence of amyloid â (Aâ) plaques in the brain. Aâ derives from proteolytic cleavage of amyloid precursor protein (APP) by b- (BACE) and ã-secretases. On the other hand, á-secretase cleaves APP within the Aâ domain generating a soluble fragment (sAPPá) which shows neuroprotective effects and improves memory. ADAM-10 and ADAM-17 metalloproteases have been identified as the main á-secretases expressed in the brain. Group II metabotropic glutamate receptors (mGluR) include mGlu3R and mGlu2R, being mGlu3R expressed in astrocytes. Astroglial mGlu3R activation reduces neuronal degeneration induced by Aâ in vitro. Although it has been shown that a non-selective agonist of mGluR promotes the non-amyloidogenic pathway in astrocytes, most likely by activating group II mGluR, this issue has not been further explored. Therefore, we studied the involvement of mGlu3R in the non-amyloidogenic shedding of APP in primary cultured rat astrocytes. The mGlu3R-selective agonist LY379268 increased sAPPá release from astrocytes in a dose-dependent manner (LY0.01 µM p<0.05; LY0.1 µM and LY10 µM p<0.01 versus control). In congruence with these results, ADAM-10 and ADAM-17 gene and protein expression was induced by LY379268 (0.1-10 mM), as assassed by qRT-PCR and western-blot (ADAM-17: LY 0.1 and 1 mM p<0.01; LY 10 mM p<0.05; ADAM-10: LY 0.1 and 10 mM p<0.05; LY 1 mM p<0.001 versus control). Conversely, BACE1 protein levels were significantly reduced after LY379268 treatment (LY 0.1 and 10 mM p<0.001; LY 1 mM p<0.05 versus control). The effect of LY379268 on sAPPa production was not observed in the presence of an antagonist of the peroxisome proliferator activated receptor (PPAR)-g (GW9662 2 mM). Surprisingly, LY379268 reduced PPAR-g protein expression (LY 0.1 mM p<0.05; LY1 and 10 mM p<0.001), thus further study is needed to clarify the involvement of this nuclear receptor in the non-amyloidogenic shedding of astroglial APP. Our data indicate that mGlu3R activation promotes the non-amyloidogenic pathway, shifting APP proteolysis towards sAPPá production in astrocytes, through ADAM-10 and ADAM-17 up-regulation and BACE1 down-regulation. This study provides evidence for a new molecular mechanism accounting for the neuroprotective effects of astrocytic mGlu3R on Aâ neurotoxicity.