Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease.
Mounting evidence indicates that impairments of synaptic efficacy and/or plasticity may be a key step in the development of Alzheimer's disease (AD) pathophysiology. Among the 2 major forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), much less is known about how LTD is regulated in AD and its molecular mechanisms. Recent studies indicate that metabotropic glutamate receptor 5 (mGluR5) may function as a receptor and/or co-receptor for amyloid beta. Herein, we examined mGluR-LTD in hippocampal slices from aged APP/PS1 mutant mice that model AD. Our findings demonstrate that mGluR-LTD is blocked in APP/PS1 mice, and that the mGluR-LTD failure is reversed by either genetically or pharmacologically suppressing the activity of PERK, a kinase for the mRNA translation factor eIF2α. These data are congruent with recent evidence that inhibition of eIF2α phosphorylation via PERK suppression and reversal of de novo protein synthesis deficits can mitigate cognitive deficits in neurodegenerative diseases. Together with reports indicating that mGluR5 may mediate amyloid beta synaptotoxicity, our findings offer insights into novel therapeutic targets for AD and other cognitive syndromes.
Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Wenzhong
W
Yang
Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Xueyan
X
Zhou
Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Helena R
HR
Zimmermann
Department of Biology, Pennsylvania State University, University Park, PA, USA.
Douglas R
DR
Cavener
Center for Neural Science, New York University, New York, NY, USA.
Eric
E
Klann
Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, USA. Electronic address: tma@wakehealth.edu.
Tao
T
Ma
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003071:Cognition; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D017774:Long-Term Potentiation / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000235:genetics; D008297:Male; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D064529:Receptor, Metabotropic Glutamate 5 / Q000502:physiology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
D016229:Amyloid beta-Peptides; D017346:Protein Serine-Threonine Kinases; D064529:Receptor, Metabotropic Glutamate 5; D019892:eIF-2 Kinase; C531557:eIF2alpha kinase, mouse
Alzheimer's disease; PERK; Protein synthesis; Synaptic plasticity; eIF2α; mGluR-LTD