Metabotropic glutamate receptor 3 activation promotes non-amyloidogenic shedding

DANIELA DURAND; LILA CARNIGLIA; CARLA CARUSO; MERCEDES LASAGA

Buenos Aires

Congreso; 2º Simposio Franco-Argentino de Neurociencias; 2012

Alzheimer’s disease is characterized by the presence of amyloid β (Aβ) plaques in the brain. Aβ derives from proteolytic cleavage of amyloid precursor protein (APP) by BACE and γ-secretase. On the other hand, α-secretase cleaves APP within the Aβ domain generating a soluble fragment (sAPPα) which shows neuroprotective actions and improves memory. ADAM-10 and ADAM-17 metalloproteases have been identified as the main α-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 Aβ 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 sAPPα release from astrocytes in a dose-dependent manner (LY0.01 µM p