Apolipoprotein E4 (APOE4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of...

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Bibliographic Details
Published in:Molecular & cellular proteomics 2016-07, Vol.15 (7), p.2252-2262
Main Authors: Sweet, Robert A., MacDonald, Matthew L., Kirkwood, Caitlin M., Ding, Ying, Schempf, Tadhg, Jones-Laughner, Jackie, Kofler, Julia, Ikonomovic, Milos D., Lopez, Oscar L., Garver, Megan E., Fitz, Nicholas F., Koldamova, Radosveta, Yates, Nathan A.
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Apolipoprotein E4 - genetics
Down-Regulation
Female
Glutamic Acid - metabolism
Humans
Male
Mass Spectrometry
Middle Aged
Prefrontal Cortex - metabolism
Proteomics - methods
Receptors, Glutamate - metabolism
Signal Transduction
Synapses - metabolism
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Summary:It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of 59 AD subjects with mild to moderate dementia and 12 normal elderly subjects was assayed using targeted mass spectrometry to quantify 191 synaptically expressed proteins. The profile of synaptic protein expression clustered AD subjects into two groups. One of these was characterized by reduced expression of glutamate receptor proteins, significantly increased synaptic protein network coexpression, and associated withApolipoprotein E*4 (APOE*4) carrier status. The second group, by contrast, showed few differences from control subjects. A subset of AD subjects had altered prefrontal cortex synaptic proteostasis for glutamate receptors and their signaling partners. Efforts to therapeutically target glutamate receptors in AD may have outcomes dependent on APOE*4 genotype.
ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M115.056580