A TWO-PRONGED APPROACH AGAINST ALZHEIMER'S DISEASE NEURODEGENERATION: AMYLOID-BETA SYNTHESIS AND CLEARANCE ARE BOTH REGULATED BY GLIAL METABOTROPIC GLUTAMATE RECEPTOR 3.

DURAND DANIELA

Mar del Plata

Congreso; XXX Annual Meeting SAN; 2015

SAN

Astrocytes are now undoubtedly endorsed as key players in the maintenance of CNS functionality and plasticity and they may aid in the resolution of neuronal damage caused by several injuries. Group II Metabotropic Glutamate Receptors (mGluR) includes mGlu3R and mGlu2R subtypes, among which only mGlu3R is expressed in astrocytes. Increasing evidence suggests that astroglial mGlu3R activation leads to neuroprotective effects. Here we show that mGlu3R activation by LY379268 promotes the alpha or non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes1, which leads to increased release of the neuroprotective soluble fragment sAPPα, while impairing amyloid beta (Aβ) production. This effect is related to the increase in ADAM10 and ADAM17 levels and the reduction in BACE1 expression, and is dependent on PPAR-γ activation1. mGlu3R activation also induces BDNF expression in astrocytes. Furthermore, mGlu3R expression was significantly diminished in hippocampal astrocytes from PDAPP-J20 transgenic mice1, a well-established model of AD, a finding which is consistent with a role for these receptors in avoiding AD progression. We next evaluated the impact of mGlu3R-induced glial soluble neurotrophins on Aβ-challenged hippocampal neurons. Using immunodepleted conditioned media we found that astrocyte-derived sAPPα and BDNF are both involved in neuroprotection exerted by astroglial mGluR3 activation after Aβ insult. Interestingly, mGlu3R activation in both astrocytes and microglia increases the rate of Aβ and latex bead uptake. Altogether these results indicate a double function for glial mGlu3R activation against Aβ neurotoxicity: (i) it promotes α-cleavage of APP and increases sAPPα and BDNF levels, and (ii) it induces amyloid removal from the extracellular space by glial phagocytic mechanisms. These findings suggest that glial mGlu3R activation may hold therapeutic value in AD. 1Durand et al 2014 Neuropharmacol.79:180-189