Metabotropic glutamate receptor 3 activation promotes non-amyloidogenic shedding of amyloid precursor protein in astrocytes.

DURAND DANIELA; CARNIGLIA LILA; CARUSO CARLA; LASAGA MERCEDES

Buenos Aires

Simposio; 2do. Simposio Franco-Argentino de Neurociencias; 2012

Sociedad Argentina de Neurociencias y Société des 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 BACE and ã-secretase. On the other hand, á-secretase cleaves APP within the Aâ domain generating a soluble fragment (sAPPá) which shows neuroprotective actions and improves memory. ADAM-10 and ADAM-17 metalloproteases have been identified as the main á-secretases in the brain. Group II metabotropic glutamate receptors (mGluR) includes mGlu3R and mGlu2R, being mGlu3R expressed in astrocytes. It has been demonstrated that a non-selective agonist of mGluR promotes the non-amyloidogenic pathway in astrocytes, most likely by activating group II mGluR. Moreover, mGlu3R stimulation in astrocytes reduces neuronal degeneration induced by Aâ in vitro. 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 assayed 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). 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.