Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease.
The dysfunction and loss of synapses in Alzheimer disease are central to dementia symptoms. We have recently demonstrated that pathological Amyloid β oligomer (Aβo) regulates the association between intracellular protein mediators and the synaptic receptor complex composed of cellular prion protein (PrP(C)) and metabotropic glutamate receptor 5 (mGluR5). Here we sought to determine whether Aβo alters the physiological signaling of the PrP(C)-mGluR5 complex upon glutamate activation. We provide evidence that acute exposure to Aβo as well as chronic expression of familial Alzheimer disease mutant transgenes in model mice prevents protein-protein interaction changes of the complex induced by the glutamate analog 3,5-dihydroxyphenylglycine. We further show that 3,5-dihydroxyphenylglycine triggers the phosphorylation and activation of protein-tyrosine kinase 2-β (PTK2B, also referred to as Pyk2) and of calcium/calmodulin-dependent protein kinase II in wild-type brain slices but not in Alzheimer disease transgenic brain slices or wild-type slices incubated with Aβo. This study further distinguishes two separate Aβo-dependent signaling cascades, one dependent on extracellular Ca(2+) and Fyn kinase activation and the other dependent on the release of Ca(2+) from intracellular stores. Thus, Aβo triggers multiple distinct PrP(C)-mGluR5-dependent events implicated in neurodegeneration and dementia. We propose that targeting the PrP(C)-mGluR5 complex will reverse aberrant Aβo-triggered states of the complex to allow physiological fluctuations of glutamate signaling.
From the Cellular Neuroscience, Neurodegeneration, and Repair Program, Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06536 and the Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074 Tübingen, Germany.
Laura T
LT
Haas
From the Cellular Neuroscience, Neurodegeneration, and Repair Program, Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06536 and stephen.strittmatter@yale.edu.
Stephen M
0000-0001-8188-3092
SM
Strittmatter
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C578936:Grm5 protein, mouse; D010446:Peptide Fragments; D018621:PrPC Proteins; D064529:Receptor, Metabotropic Glutamate 5; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid
Alzheimer disease; Ca2+/calmodulin-dependent protein kinase II (CaMKII); amyloid β; homer; metabotropic glutamate receptor (mGluR); prion; pyk2