Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Manavalan, Arulmani; Mishra, Manisha; Sze, Siu Kwan; Heese, Klaus

doi:10.1159/000343672

Cited by 16 publications

(7 citation statements)

References 112 publications

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“…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%

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

Nayak²,

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Nayak²,

et al. 2017

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“…A similar method was also used to determine if the proteins that were detected in our neuronal sample had been previously associated with AD. A second compilation of AD-associated proteins was established that combined the results from studies that identified proteins in neurofibrillary tangles 7 8 9 , proteins up-regulated in plaques 14 , proteins that had significantly altered expression in various regions and/or fractions of the AD brain in comparison to control brains 10 15 16 17 18 19 20 21 22 23 24 25 and all proteins that contained the keyword “Alzheimer” in the UniProt human database (accessed 9/4/14). It was found that 209 of our total identified 399 proteins (52%) had previously been associated with AD ( supplementary Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of neurons microdissected from formalin-fixed, paraffin-embedded Alzheimer’s disease brain tissue

Drummond

Nayak

Ueberheide

et al. 2015

Sci Rep

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The vast majority of human tissue specimens are formalin-fixed, paraffin embedded (FFPE) archival samples, making this type of tissue a potential gold mine for medical research. It is now accepted that proteomics can be done using FFPE tissue and can generate similar results as snap-frozen tissue. However, the current methodology requires a large amount of starting protein, limiting the questions that can be answered in these types of proteomics studies and making cell-type specific proteomics studies difficult. Cell-type specific proteomics has the potential to greatly enhance understanding of cell functioning in both normal and disease states. Therefore, here we describe a new method that allows localized proteomics on individual cell populations isolated from FFPE tissue sections using laser capture microdissection. To demonstrate this technique we microdissected neurons from archived tissue blocks of the temporal cortex from patients with Alzheimer’s disease. Using this method we identified over 400 proteins in microdissected neurons; on average 78% that were neuronal and 50% that were associated with Alzheimer’s disease. Therefore, this technique is able to provide accurate and meaningful data and has great potential for any future study that wishes to perform localized proteomics using very small amounts of archived FFPE tissue.

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“…It is noteworthy that decreased KCC2 expression has been observed in the hippocampus AD11 mice which express an anti-NGF antibody and develop AD-like hallmarks including amyloid deposits 65 . In addition, mice overexpressing p60TRP, a G-protein coupled receptor known to promote non-amyloidogenic processing of APP, bare an increase in KCC2 expression 66 . Given these observations, it would be interesting to investigate whether these KCC2 expression changes could be linked to a dysregulation in APP processing.…”

Section: Discussionmentioning

confidence: 99%

Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission

Doshina

Gourgue

Onizuka

et al. 2017

Sci Rep

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The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na+-K+-2Cl− cotransporter 1 (NKCC1) and neuronal K+-Cl− cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission.

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Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Cited by 16 publications

References 112 publications

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

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

Proteomic analysis of neurons microdissected from formalin-fixed, paraffin-embedded Alzheimer’s disease brain tissue

Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission

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