ly-341495 and Alzheimer-Disease

Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic β-amyloid protein (Aβ) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Aβ-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Aβ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Aβ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Aβ, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Aβ-induced toxicity.

Topics: Alzheimer Disease; Amino Acids; Amyloid beta-Peptides; Animals; Antipsychotic Agents; Astrocytes; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Psychotic Disorders; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Transforming Growth Factor beta1; Xanthenes

Aberrant accumulation of amyloid beta (Abeta) oligomers may underlie the cognitive failure of Alzheimer's disease (AD). All species of Abeta peptides are produced physiologically during normal brain activity. Therefore, elucidation of mechanisms that interconnect excitatory glutamatergic neurotransmission, synaptic amyloid precursor protein (APP) processing and production of its metabolite, Abeta, may reveal synapse-specific strategies for suppressing the pathological accumulation of Abeta oligomers and fibrils that characterize AD. To study synaptic APP processing, we used isolated intact nerve terminals (cortical synaptoneurosomes) from TgCRND8 mice, which express a human APP with familial AD mutations. Potassium chloride depolarization caused sustained release from synaptoneurosomes of Abeta(42) as well as Abeta(40), and appeared to coactivate alpha-, beta- and gamma-secretases, which are known to generate a family of released peptides, including Abeta(40) and Abeta(42). Stimulation of postsynaptic group I metabotropic glutamate receptor (mGluRs) with DHPG (3,5-dihydroxyphenylglycine) induced a rapid accumulation of APP C-terminal fragments (CTFs) in the synaptoneurosomes, a family of membrane-bound intermediates generated from APP metabolized by alpha- and beta-secretases. Following stimulation with the group II mGluR agonist DCG-IV, levels of APP CTFs in the synaptoneurosomes initially increased but then returned to baseline by 10 min after stimulation. This APP CTF degradation phase was accompanied by sustained accumulation of Abeta(42) in the releasate, which was blocked by the group II mGluR antagonist LY341495. These data suggest that group II mGluR may trigger synaptic activation of all three secretases and that suppression of group II mGluR signaling may be a therapeutic strategy for selectively reducing synaptic generation of Abeta(42).

Topics: Alzheimer Disease; Amino Acids; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Humans; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Nerve Endings; Peptide Fragments; Receptors, Metabotropic Glutamate; Signal Transduction; Xanthenes