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Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.

Williams C, Mehrian Shai R, Wu Y, Hsu YH, Sitzer T, Spann B, McCleary C, Mo Y, Miller CA - PLoS ONE (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
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.

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Related in: MedlinePlus

Quantitative RT-PCR confirms upregulation of GLUT1 and GluR2.Total RNA (2 µg) was used to generate cDNA by reverse transcription using oligo-dT primers. Note increased mRNA levels of glutamate transporter (GLUT1) and GluR2 in IAD patients compared to controls. Data are mean values ±SEM comparing 4 control and 4 IAD patients. βCAMKII and GAP43 do not show significant change in mRNA levels. GAP-3 (p<0.1), GLUT1 (* p<0.01), GluR2 (# p<0.03), βCAMKII (p<0.06).
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pone-0004936-g004: Quantitative RT-PCR confirms upregulation of GLUT1 and GluR2.Total RNA (2 µg) was used to generate cDNA by reverse transcription using oligo-dT primers. Note increased mRNA levels of glutamate transporter (GLUT1) and GluR2 in IAD patients compared to controls. Data are mean values ±SEM comparing 4 control and 4 IAD patients. βCAMKII and GAP43 do not show significant change in mRNA levels. GAP-3 (p<0.1), GLUT1 (* p<0.01), GluR2 (# p<0.03), βCAMKII (p<0.06).

Mentions: To quantify the differential expression patterns determined by microarray, synaptoneurosome mRNA from 5 control and 5 IAD patients was tested by quantitative RT-PCR. Genes selected from the microarray data set represented a spectrum of function. Quantitative RT-PCR analyses confirmed the mRNA expression changes detected in the microarray between control and IAD patients (Figure 4) and indicate a higher fold change in IAD with, GLUT1 (×3.0, p<0.01) and GluR2 (×3.5, p<0.03).


Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer's disease.

Williams C, Mehrian Shai R, Wu Y, Hsu YH, Sitzer T, Spann B, McCleary C, Mo Y, Miller CA - PLoS ONE (2009)

Quantitative RT-PCR confirms upregulation of GLUT1 and GluR2.Total RNA (2 µg) was used to generate cDNA by reverse transcription using oligo-dT primers. Note increased mRNA levels of glutamate transporter (GLUT1) and GluR2 in IAD patients compared to controls. Data are mean values ±SEM comparing 4 control and 4 IAD patients. βCAMKII and GAP43 do not show significant change in mRNA levels. GAP-3 (p<0.1), GLUT1 (* p<0.01), GluR2 (# p<0.03), βCAMKII (p<0.06).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654156&req=5

pone-0004936-g004: Quantitative RT-PCR confirms upregulation of GLUT1 and GluR2.Total RNA (2 µg) was used to generate cDNA by reverse transcription using oligo-dT primers. Note increased mRNA levels of glutamate transporter (GLUT1) and GluR2 in IAD patients compared to controls. Data are mean values ±SEM comparing 4 control and 4 IAD patients. βCAMKII and GAP43 do not show significant change in mRNA levels. GAP-3 (p<0.1), GLUT1 (* p<0.01), GluR2 (# p<0.03), βCAMKII (p<0.06).
Mentions: To quantify the differential expression patterns determined by microarray, synaptoneurosome mRNA from 5 control and 5 IAD patients was tested by quantitative RT-PCR. Genes selected from the microarray data set represented a spectrum of function. Quantitative RT-PCR analyses confirmed the mRNA expression changes detected in the microarray between control and IAD patients (Figure 4) and indicate a higher fold change in IAD with, GLUT1 (×3.0, p<0.01) and GluR2 (×3.5, p<0.03).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Keck School of Medicine University of Southern California, Los Angeles, California, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus