Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.
Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.
Center for Neural Science, New York University, New York, New York, USA.
Tao
T
Ma
Mimi A
MA
Trinh
Alyse J
AJ
Wexler
Clarisse
C
Bourbon
Evelina
E
Gatti
Philippe
P
Pierre
Douglas R
DR
Cavener
Eric
E
Klann
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D000841:Anisomycin; D053764:Presenilin-1; D011500:Protein Synthesis Inhibitors; D019892:eIF-2 Kinase; C508853:PSEN1 protein, human