Group II metabotropic glutamate receptor stimulation triggers production and release of Alzheimer's amyloid(beta)42 from isolated intact nerve terminals.
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).
Departments of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Soong Ho
SH
Kim
Paul E
PE
Fraser
David
D
Westaway
Peter H
PH
St George-Hyslop
Michelle E
ME
Ehrlich
Sam
S
Gandy
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D006801:Humans; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009411:Nerve Endings / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C114624:LY 341495; D010446:Peptide Fragments; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C075222:amyloid beta-protein (1-42); C108822:metabotropic glutamate receptor 2; D008734:Methoxyhydroxyphenylglycol; D053829:Amyloid Precursor Protein Secretases; C010117:3,4-dihydroxyphenylglycol