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

Sweet, Robert A.; MacDonald, Matthew L.; Kirkwood, Caitlin M.; Ding, Ying; Schempf, Tadhg; Jones-Laughner, Jackie; Kofler, Julia; Ikonomović, Miloš D.; López, Oscar L.; Garver, Megan; Fitz, Nicholas F.; Koldamova, Radosveta; Yates, Nathan A.

doi:10.1074/mcp.m115.056580

Cited by 31 publications

(25 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies of PreC in AD reported loss of total synapse numbers at the ultrastructural level (Scheff et al, 2013) and loss of postsynaptic protein PSD-95 (Gylys et al, 2004). With several notable exceptions (Sweet et al, 2016), loss of postsynaptic proteins was also reported in other cortical areas in AD. Using Western blot analysis, loss of the postsynaptic protein drebrin was reported in the superior frontal, superior temporal, and visual cortex as well as the hippocampus in mAD (Counts et al, 2006, 2012).…”

Section: Discussionmentioning

confidence: 89%

Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease

Abrahamson

Ryu

et al. 2017

Neurobiology of Aging

Self Cite

View full text Add to dashboard Cite

Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer’s disease (AD), and this pathology may be associated with alterations in PreC synapses and cognitive impairment. We quantified the spinophilin-immunoreactive (ir) dendritic spine density and the intensity of spinophilin immunofluorescence, the latter as a measure of relative protein levels of spinophilin, in PreC lamina III from 33 subjects with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or severe AD (sAD). Both measures of spinophilin were lower in mAD and sAD compared with NCI. The MCI group had higher protein levels of spinophilin compared with mAD and sAD, and higher spinophilin-ir dendritic spine density compared with sAD. Lower spinophilin-ir dendritic spine density and relative protein levels of spinophilin were associated with greater amyloid beta (Aβ) plaque burden, detected with a derivative of Pittsburgh compound-B (6-CN-PiB), and worse cognitive performance. Clinical onset of AD is marked by the loss of PreC spinophilin-ir dendritic spines that is related to Aβ pathology and may contribute to cognitive symptoms early in the disease.

show abstract

Section: Discussionmentioning

confidence: 89%

Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease

Abrahamson

Ryu

et al. 2017

Neurobiology of Aging

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, the significantly altered proteins in rpAD plaques were compared to our database of AD associated proteins identified in previous proteomic studies[1, 2, 4, 11, 13, 14, 22, 31–33, 36, 37, 43, 45, 50, 54, 55, 66, 77, 78, 82, 89, 90, 96]. In this database we annotated proteins as up-regulated in AD, down-regulated in AD and proteins that are enriched in plaques or tangles (Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…This database combined the results from studies that identified proteins in neurofibrillary tangles[50, 66, 82], proteins enriched in plaques[32, 43], proteins that had significantly altered expression in various regions and/or fractions of AD brains in comparison to control brains and proteins that contained the keyword “Alzheimer” in the Uniprot human database[1, 2, 4, 11, 13, 14, 22, 31–33, 36, 37, 45, 54, 55, 77, 78, 89, 90, 96]. Protein groups identified in rpAD and sAD plaques were screened against this database to determine how many of the proteins identified in this study have been previously associated with AD pathology.…”

Section: Methodsmentioning

confidence: 99%

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Nayak²,

et al. 2017

View full text Add to dashboard Cite

Rapidly progressive Alzheimer’s disease (rpAD) is a particularly aggressive form of Alzheimer’s disease, with a median survival time of 7–10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer’s disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer’s disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n=22 for each patient group) and protein expression differences were quantified. On average, 913±30 (mean±SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p=0.0017) and significantly lower levels of astrocyte proteins (p=1.08x10−6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provides new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer’s disease.

show abstract

“…Other recent clinical evidence also supports this result: for instance, a recent longitudinal study of CSF biomarkers found that APOE4 genotype influences dramatically markers of neuronal injury inducing a constant increase of CSF t-tau and p-tau181 levels 36 , and higher CSF tau levels were specifically correlated with increased tau in the temporal lobe, a region involved in memory processing 38 . Indeed, there is an increased risk of progression from mild cognitive impairment to AD with elevated CSF t-tau and p-tau and with the presence of the APOE4 genotype, but not with decreased CSF Aβ42 levels 39 . Moreover, APOE4 may accelerate onset of dementia and neuronal degeneration by differentially impairing the maintenance of synaptic strength and reducing glutamate signaling proteins, even in the absence of overexpression of APP and Aβ APOE4 39 .…”

Section: Discussionmentioning

confidence: 99%

CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer’s disease

Koch

Lorenzo

Loizzo³

et al. 2017

Sci Rep

View full text Add to dashboard Cite

In Alzheimer’s disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau.

show abstract

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

Cited by 31 publications

References 54 publications

Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease

Loss of precuneus dendritic spines immunopositive for spinophilin is related to cognitive impairment in early Alzheimer's disease

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer’s disease

Contact Info

Product

Resources

About