Neuroprotective Action Of Group Ⅲ Metabotropic Glutamate Receptors Against Neuronal Apoptosis, With Special Reference To Modulation On Neuronal [Ca～(2+)]i Induced By β-amyloid Peptide 31-35

Alzheimer's disease is a neurodegenerative disorder, characterized by senile plaques, neurofibrillary tangle, and a widespread loss of neurons, along with progressive impairment of cognition and emotional activities. Increasing evidences shown thatβ-amyloid deposition is the leading cause for AD.β-amyloid peptide(Aβ) is a 39-43-amino acid peptide that accumulated as insoluble extracellular deposits in Alzheimer's brain and is believed toxicity to neurons, is also profoundly involved in the pathogenesis of AD.Glutamate, the major excitatory transmitter in the central nervous system, activates distinct receptor subtypes, broadly distinguished into two general groups, named ionotropic and metabotropic receptors. Metabotropic glutamate receptors(mGluRs) are coupled to G proteins and act on various intracellular second messenger systems. mGluRs are generally classified into three classes according to their sequence homology,coupling to transduction mechanisms and pharmacological agents. Group I(mGluR1, mGluR5) mGluRs are mainly located postsynaptically, and stimulate phospholipase C and phosphoinositide hydrolysis, and their postsynaptic response are similar to NMDA receptor in many ways. Group II(mGluR2, mGluR3) and especially group III(mGluR4, mGluR6, mGluR6, mGluR7, mGluR8) mGluRs are overwhelmingly located presynaptically, and negatively couple to adenyly cyclase ,and in turn inhibit cAMP formation. It has been reported that these presynaptic receptor are involved in synaptic transmission by negative feedback of releasing glutamate. In this way, prevention or protection neurons from the neurotoxicity by overreleasing or overactivation of NMDA receptors . Recently, Bruno et al reported that activation of group III mGluRs protect neurons against excitotoxic death in vitro; Copani et al have demonstrated that activation of group III mGluRs protect cultured neurons against apoptosis induced by Aβ25-35. Aβ31-35, an even smaller amyloid peptide fragment has been reported possesses the similar toxicity as full length...