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

Full 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.

Author information

Author/s: Williams, Celia (C); 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);

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

Grants: 2P50 AG005142 (Agency:NIA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: PloS one (PLoS One), published in United States. (Language: eng)

Reference: 2009-; vol 4 (issue 3) : pp e4936

Dates: Created 2009/03/19; Completed 2009/05/14; Revised 2009/06/16;

PMID: 19295912, status: MEDLINE (last retrieved date: 6/16/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Alzheimer Disease - genetics; metabolism; pathology; physiopathology
Amyloid beta-Protein - genetics; metabolism
Cluster Analysis
Cognition - physiology
Disease Progression
Gene Expression Profiling
Humans
Microarray Analysis
Neuronal Plasticity - genetics

Neuronal Plasticity - genetics
Neurons - physiology; ultrastructure
Neuropsychological Tests
Prefrontal Cortex - pathology; physiology
RNA, Messenger - analysis
Receptor, Muscarinic M3 - genetics; metabolism
Receptors, AMPA - genetics; metabolism
Synapses - metabolism; ultrastructure
Synaptosomes - physiology; ultrastructure

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Amyloid beta-Protein (0) ; RNA, Messenger (0) ; Receptor, Muscarinic M3 (0) ; Receptors, AMPA (0) ; glutamate receptor ionotropic, AMPA 2 (0)

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