Apolipoprotein E*4 (APOE*4) 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 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.
From the Departments of ‡Psychiatry, **Neurology, and ‡‡VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC) and sweetra@upmc.edu.
Robert A
RA
Sweet
From the Departments of ‡Psychiatry.
Matthew L
ML
MacDonald
From the Departments of ‡Psychiatry.
Caitlin M
CM
Kirkwood
§Biostatistics.
Ying
Y
Ding
From the Departments of ‡Psychiatry.
Tadhg
T
Schempf
¶Cell Biology.
Jackie
J
Jones-Laughner
‖Pathology.
Julia
J
Kofler
**Neurology, and §§Geriatric Research, Education and Clinical Center (GRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA.
Milos D
MD
Ikonomovic
From the Departments of ‡Psychiatry, **Neurology, and.
Oscar L
OL
Lopez
From the Departments of ‡Psychiatry.
Megan E
ME
Garver
¶¶Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA;
Nicholas F
NF
Fitz
¶¶Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA;
Radosveta
R
Koldamova
¶Cell Biology.
Nathan A
NA
Yates
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics*; D015536:Down-Regulation; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D017470:Receptors, Glutamate / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
D053327:Apolipoprotein E4; D017470:Receptors, Glutamate; D018698:Glutamic Acid