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Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression - PubMed

  • ️Sun Jan 01 2017

Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression

Mercedes Lachén-Montes et al. Sci Rep. 2017.

Abstract

Olfactory dysfunction is among the earliest features of Alzheimer's disease (AD). Although neuropathological abnormalities have been detected in the olfactory bulb (OB), little is known about its dynamic biology. Here, OB- proteome analysis showed a stage-dependent synaptic proteostasis impairment during AD evolution. In addition to progressive modulation of tau and amyloid precursor protein (APP) interactomes, network-driven proteomics revealed an early disruption of upstream and downstream p38 MAPK pathway and a subsequent impairment of Phosphoinositide-dependent protein kinase 1 (PDK1)/Protein kinase C (PKC) signaling axis in the OB from AD subjects. Moreover, a mitochondrial imbalance was evidenced by a depletion of Prohibitin-2 (Phb2) levels and a specific decrease in the phosphorylated isoforms of Phb1 in intermediate and advanced AD stages. Interestingly, olfactory Phb subunits were also deregulated across different types of dementia. Phb2 showed a specific up-regulation in mixed dementia, while Phb1 isoforms were down-regulated in frontotemporal lobar degeneration (FTLD). However, no differences were observed in the olfactory expression of Phb subunits in progressive supranuclear palsy (PSP). To sum up, our data reflect, in part, the missing links in the biochemical understanding of olfactory dysfunction in AD, unveiling Phb complex as a differential driver of neurodegeneration at olfactory level.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1

Differentially expressed proteins in the OB across AD-related phenotypes. (a) Volcano plots representing the fold-change of identified proteins with associated P values from the pair-wise quantitative comparisons of control vs initial AD stage (upper panel), control vs intermediate AD stage (middle panel), and control vs advanced AD stage (lower panel). In green, very significantly changed proteins (P < 0.01), in yellow, significantly changed proteins (P < 0.05) and in blue, unchanged proteins between the pair-wise comparisons. (b) Differential olfactory proteome distribution across AD stages. (c) Venn diagram of common and unique differential proteins between AD stages. The distribution of common and distinct proteins in initial, intermediate, and advanced stages is shown.

Figure 2
Figure 2

Functional metrics of the differential OB proteome across AD staging. Specific-neuronal pathway analysis for the differential OB proteomic expression profile detected in each AD stage is shown.

Figure 3
Figure 3

High-scoring protein interactome maps for differentially expressed proteins in the OB during AD progression. Visual representation of the relationships between differential expressed proteins and functional interactors in initial (a), intermediate (b), and advanced AD stages (c). Dysregulated proteins are highlighted in red (up-regulated) and green (down-regulated) for each stage. Continuous and discontinuous lines represent direct and indirect interactions respectively. The complete legend including main features, molecule shapes, and relationships is found in

http://ingenuity.force.com/ipa/articles/Feature_Description/Legend

.

Figure 4
Figure 4

Signaling pathways disrupted in the OB across AD grading. Levels and residue-specific phosphorylation of MKK3/6 (a), p38 MAPK, ATF2, and HSP27 (b), PDK1, and PKC (c) in the OB across AD phenotypes. Equal loading of the gels was assessed by Ponceau staining and hybridization with a GAPDH specific antibody. Right panels show histograms of band densities. Data are presented as mean ± SEM from 5 independent OB samples per group. *P < 0.05 vs control group; **P < 0.01 vs control group. Representative Western blot gels (n = 3/experimental group) are shown. Full-length blots/gels are presented in Supplementary information.

Figure 5
Figure 5

Functional interactome distribution across AD stages. The number of predicted functional interactors for hub proteins with impact in neurobiology is represented.

Figure 6
Figure 6

Immunohistochemical localization of OB Vim, Phb1 and Phb2 across AD grading. First line: Representative immunohistochemical staining pattern of Vim across AD grading. Positive staining in glomerular cell layer (GL) and wall of endothelial cells (ovals). Second line: Representative immunohistochemical staining pattern of Phb1 across AD grading. Positive staining in glomerular layer (GL), anterior olfactory nucleus (AON), and mitral cells (asterisks). Third line: Representative immunohistochemical staining pattern of Phb2 across AD grading. Positive staining in glomerular layer (GL), anterior olfactory nucleus (AON), and mitral cells (asterisks).

Figure 7
Figure 7

Olfactory expression of Vim and Phb subunits across AD stages. (a) Protein levels of Vim, Phb2, and Phb1 were monitored by Western-blotting. Equal loading of the gels was assessed by Ponceau staining and hybridization with a GAPDH specific antibody. Representative Western blot gels (n = 3/experimental group) are shown (left). Right panels show histograms of band densities. Data are presented as mean ± SEM from 3 independent OB samples per group. *P < 0.05 vs control group; ***P < 0.001 vs control group. (b) OB phosphorylation profiling of PHb1 across AD staging. Representative Western blot gels (n = 2/experimental group) are shown (left). Right panel shows histograms of band densities. Data are presented as mean ± SEM from 3 independent OB samples per group. *P < 0.05 vs control group; **P < 0.01 vs control group. Full-length blots/gels are presented in Supplementary information.

Figure 8
Figure 8

OB protein expression of Phb isoforms across AD-related proteinopathies. Olfactory expression of Phb2, Phb1, and Phb1 phosphorylated isoforms in Mix AD VD (a), FTLD (b), and PSP (c). Representative Western blot gels are shown for each Phb subunit. Histograms of band densities derived from 28 independent OB samples. Data are presented as mean ± SEM from: Controls (n = 4 cases), mixed dementia (mix AD VD) (n = 9 cases), FTLD (n = 6 cases), and PSP (n = 9 cases). *P < 0.05 vs control group; **P < 0.01 vs control group. Full-length blots/gels are presented in Supplementary Information.

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