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. 2023 Aug 9;24(16):12606.
doi: 10.3390/ijms241612606.

The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer's Disease Reveals New Insights for AD Study

Lory J Rochín-Hernández  1 , Miguel A Jiménez-Acosta  1 , Lorena Ramírez-Reyes  2 , María Del Pilar Figueroa-Corona  1 , Víctor J Sánchez-González  3 , Maribel Orozco-Barajas  3 , Marco A Meraz-Ríos  1
Affiliations

The Proteome Profile of Olfactory Ecto-Mesenchymal Stem Cells-Derived from Patients with Familial Alzheimer's Disease Reveals New Insights for AD Study

Lory J Rochín-Hernández et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer's Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.

Keywords: A431E; Alzheimer’s disease; FAD; Familial Alzheimer’s disease; PSEN1; mesenchymal stem cells; neurodegeneration; olfactory; proteome; proteostasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart for the study’s process. Olfactory ecto-mesenchymal stem cells were gathered and cultivated from two PSEN1 (A431E) mutant carriers and two healthy donors. MSC markers were then determined using flow cytometry. Protein was isolated and digested to identify DEPs by stage (symptomatic and presymptomatic) using two label-free proteomic techniques (P1/C1 and P2/C2). Data quality control and filtering were carried out to demonstrate proper reliability and confidence in the outcomes. Each protein group was subjected to functional analysis and comparisons using various bioinformatics techniques.
Figure 2
Figure 2
Nine passes of nasal exfoliation result in cells expressing mesenchymal markers. (A) The symptomatic mutation carrier (P1) showed in red. Its control (C1) is in blue, (B) dot plots of cells from presymptomatic mutation carrier (P2) are shown in orange, and its control (C2) is in green. Cells labeled with markers for CD34, CD105, CD73, CD90, CD45, CD14, CD166, and CD19 are shown in a cell morphology dot plot.
Figure 3
Figure 3
Dependability and confidence of peptides and proteins (P1/C1 and P2/C2). (A,E) histograms show the total number of peptides with an inaccuracy of no more than 5 ppm (dark blue or orange). (B,F) dot plot of PepFrag1 peptides concentrated at a maximum of 18 ppm in the case of B and 16 ppm in the case of F across the examined m/z range. (C,G) a pie graph illustrating the different types of peptides. The dynamic range of measured proteins (D,H). The Y-axis represents the average intensities for each quantified protein (expressed as log10), and the X-axis represents the number of quantified proteins (IDS).
Figure 4
Figure 4
Differentially expressed proteins in symptomatic and presymptomatic carriers related to controls. Both proteins that are upregulated (red) and downregulated (green) in all pairwise comparisons are depicted in the volcano plot (A,C). (B,D) a pie chart showing the different protein classes based on differential expression.
Figure 5
Figure 5
Gene ontology annotation of proteins produced differently in symptomatic (A–C) and presymptomatic (D,E) carrier cells compared to C1 and C2. Biological processes (A,D) cellular component (B,E) and molecular function (C,F).
Figure 6
Figure 6
Top 15 enriched pathways in P1/C1 (A) and P2/C2 (B) using WebGestalt with KEGG Database.
Figure 7
Figure 7
Protein–protein interaction (PPI) network of P1/C1 (A) and P2/C2 (B) DEPs constructed on STRING with the KEGG-enriched pathways underlined. The upper-right corner displays disconnected nodes connected to the indicated paths. Confidence rating (0.9).
Figure 8
Figure 8
PPIs of differentially expressed proteins of P1 and P2 involved in (A) protein processing in ER and (B) vesicle secretion and transport.
Figure 9
Figure 9
Summary of dysproteostasis network in PSEN1 (A431E) mutation carriers proteostasis comprises a complex network of processes that allow the maintenance of the conformation, concentration, and localization of proteins for their correct function. Our findings demonstrate that MSCs derived from carriers of the PSEN1 (A431E) mutation show a disruption of Protein Quality Control and proteostasis-like energy metabolism pathways that could lead to an increase in oxidative stress, an alteration in synthesis, folding, and degradation of proteins which could help to the accumulation and aggregation of misfolded proteins, and dysfunction of cytoskeleton organization, and intracellular and vesicular transport.
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