A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann–Pick Disease Type C
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Transcriptome Analysis
2.3. Data Preprocessing
2.4. Differential Gene Expression Analysis
2.5. Ingenuity Pathway Analysis
2.6. Gene Set Enrichment Analysis
3. Results
3.1. Loss of APP Amplifies Interferon Signaling in the Npc1−/− Cerebral Cortex and Cerebellum
3.2. APP Depletion Exacerbates Inflammatory Pathways Linked To DAMP Generation, ROS, and Lipid Peroxidation in the Npc1−/− Cerebral Cortex
3.3. The Cellular Hormetic Response to 27-Hydroxycholesterol Is Impaired Following APP Depletion in the NPC Brain
3.4. Npc1−/− Tau Hyperphosphorylation Is Exacerbated by APP Depletion
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Cortex | Cerebellum | |||||
---|---|---|---|---|---|---|
Npc1−/− | App−/− | Npc1−/− /App−/− | *Npc1−/− | App−/− | *Npc1−/− /App−/− | |
DEG (aFC + p) | 321 | 843 | 1884 | 387 | 1065 | 1973 |
DEG (up) | 199 | 459 | 1177 | 176 | 457 | 1265 |
DEG (down) | 122 | 384 | 707 | 211 | 608 | 708 |
Upstream Regulators | Npc1−/−/App−/− Ctx vs. WT Ctx | *Npc1−/− Ctx vs. WT Ctx | App−/− Ctx vs. WT Ctx | ||||||
---|---|---|---|---|---|---|---|---|---|
z-Score | −log(p) | #T.M | z-Score | −log(p) | #T.M | z-Score | −log(p) | #T.M | |
IFN-γ | 8.494 | 33.070 | 201 | 4.104 | 10.291 | 84 | −0.844 | 3.650 | 66 |
M-CSF/CSF1 | 4.257 | 41.633 | 116 | 3.785 | 5.210 | 21 | 0.588 | 1.527 | 16 |
GM-CSF/CSF2 | 4.986 | 13.799 | 73 | 3.598 | 5.000 | 33 | 1.640 | 1.565 | 22 |
IL33 | 5.102 | 17.583 | 71 | 3.036 | 2.914 | 17 | 0.927 | 2.863 | 23 |
TNFα | 6.099 | 29.403 | 238 | 2.908 | 8.028 | 96 | −0.681 | 1.376 | 71 |
IL-4 | 3.152 | 47.044 | 258 | 2.902 | 5.775 | 57 | 0.838 | 3.440 | 55 |
IL-6 | 5.230 | 26.041 | 161 | 2.737 | 5.370 | 46 | n/a | ||
IL-3 | 3.865 | 9.932 | 63 | 2.460 | 2.436 | 21 | n/a |
Upstream Regulators | *Npc1−/−/App−/− Crb vs. WT Crb | *Npc1−/− Crb vs. WT Crb | *App−/− Crb vs. WT Crb | ||||||
---|---|---|---|---|---|---|---|---|---|
z-Score | −log(p) | #T.M | z-Score | −log(p) | #T.M | z-Score | −log(p) | #T.M | |
IFN-γ | 9.324 | 38.497 | 262 | 5.432 | 21.225 | 84 | −0.152 | 2.481 | 69 |
TNFα | 6.724 | 17.390 | 258 | 4.694 | 12.412 | 81 | −0.816 | 1.324 | 79 |
IFN-α (group) | 6.567 | 14.712 | 84 | 2.981 | 11.699 | 33 | −1.845 | 0 | 12 |
GM-CSF/CSF2 | 5.761 | 8.539 | 79 | 4.023 | 5.740 | 26 | −0.239 | 2.119 | 28 |
IFN-β1 | 4.841 | 11.953 | 62 | 2.874 | 7.525 | 19 | 1.250 | 2.844 | 0 |
IL-1β | 6.972 | 13.230 | 147 | 3.828 | 9.729 | 49 | n/a | ||
IFN-α2 | 6.302 | 16.475 | 61 | 3.059 | 13.590 | 27 | n/a | ||
IFN-β (group) | 4.956 | 7.919 | 31 | 3.595 | 10.769 | 18 | n/a |
Function | *Npc1−/− Crb | *Npc1−/−App−/− Crb | *Npc1−/− Ctx | Npc1−/−App−/− Ctx |
---|---|---|---|---|
Microglial Activation | 9 | 29 | 15 | 29 |
Antiviral Response | 15 | 56 | n/a | 41 |
Antimicrobial Response | n/a | 83 | 31 | 73 |
T-lymphocyte Activation | 18 | 87 | 37 | 79 |
T-lymphocyte Chemotaxis | 6 | 25 | n/a | n/a |
Activation of Antigen-Presenting Cells | n/a | 87 | 43 | 95 |
Activation of Dendritic Cells | n/a | 27 | n/a | 25 |
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Sanchez, K.L.; Shin, S.D.; Rajagopal, N.; White, J.B.; Currais, A.; Castell, D.-S.; Maher, P.; Soriano, S. A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann–Pick Disease Type C. Genes 2024, 15, 1066. https://doi.org/10.3390/genes15081066
Sanchez KL, Shin SD, Rajagopal N, White JB, Currais A, Castell D-S, Maher P, Soriano S. A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann–Pick Disease Type C. Genes. 2024; 15(8):1066. https://doi.org/10.3390/genes15081066
Chicago/Turabian StyleSanchez, Kayla L., Samuel D. Shin, Naren Rajagopal, Jacob B. White, Antonio Currais, David-Soriano Castell, Pamela Maher, and Salvador Soriano. 2024. "A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann–Pick Disease Type C" Genes 15, no. 8: 1066. https://doi.org/10.3390/genes15081066