Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.
In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAbeta). To identify immediate molecular targets downstream of oAbeta binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Abeta (dAbeta). These patients also showed increased expression of neuroplasticity related genes, many encoding 3'UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAbeta.
Williams
Celia
C
Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, California, United States of America.
Mehrian Shai
Ruty
R
Wu
Yongchun
Y
Hsu
Ya-Hsuan
YH
Sitzer
Traci
T
Spann
Bryan
B
McCleary
Carol
C
Mo
Yi
Y
Miller
Carol A
CA
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D003071:Cognition / Q000502:physiology; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000473:pathology / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D013574:Synaptosomes / Q000502:physiology* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D043587:Receptor, Muscarinic M3; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2