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106
Figure 3.10: Trem2 and C1q deficiency independently affects Aβ proteostasis: Principal
Component analysis was performed on the 7 Aβ ELISA measurements (Top). Clustering
algorithms isolate Trem2 deficient animals apart from C1q deficient animals and are drawn on
the graph. K-means clustering algorithms indicate the number of animals in in each cluster
(Bottom).
Object Description
| Title | TREM2 and C1q signaling regulates immunoproteostasis in Alzheimer's disease |
| Author | Leung, Brian Pak Yan |
| Author email | brianple@USC.edu;brian.p.leung@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2018-08-04 |
| Date submitted | 2018-08-04 |
| Date approved | 2018-08-07 |
| Restricted until | 2018-08-07 |
| Date published | 2018-08-07 |
| Advisor (committee chair) | Finch, Caleb |
| Advisor (committee member) |
Town, Terrence Christopher Levitt, Pat Chang, Karen Tower, John |
| Abstract | Alzheimer’s disease (AD) now afflicts more than 5 million Americans, and an effective treatment or cure does not exist. Risk for late onset AD (LOAD) is likely determined by complex interplay between environmental and genetic factors. Multiple genome-wide association studies and gene network analyses have implicated two major innate immune pathways as key risk factors for late-onset Alzheimer’s disease: Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and protein complement component C1q. Further, a more recent GWAS specifically identified peripheral macrophage genes as AD risk factors. We show that both TREM2 and C1q proteins are dysregulated in AD mouse brains and in LOAD brains vs. non-demented controls. While classically thought to regulate different types of immune responses, our data raise the tantalizing possibility that the TREM2 and C1q pathways intersect in AD. Specifically, we have made the novel observation that C1q, TREM2 and Aβ physically interact, forming a heteromeric complex on innate immune cells. We further show that small Aβ assemblies preferentially bind to TREM2, while C1q more avidly associates with Aβ aggregates. In the APP/PS1 mouse model, compound genetic loss of TREM2 and C1q abrogates extracellular regulated kinase (ERK)1/2 innate immune signaling. Peripheral mononuclear phagocyte experiments demonstrate that phagocytosis of C1q opsonized Aβ is both Trem2 and pERK1/2 dependent, whereas phagocytosis of Aβ alone requires Trem2 and p-p38 mitogen activated protein kinase (MAPK). For the first time, these results shed light on the biological significance of the TREM2-C1q-Aβ neuroimmune complex in transition from the healthy CNS to the AD brain, and have key implications for myeloid Aβ phagocytosis, clearance, and immunoproteostasis. |
| Keyword | Alzheimer's disease; immunity; neuroscience; macrophage; microglia; immune system; neurodegeneration; aging; TREM2; C1q; complement; immunoproteostasis |
| Language | English |
| Format (imt) | application/pdf |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Leung, Brian Pak Yan |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-LeungBrian-6676.pdf |
| Archival file | Volume3/etd-LeungBrian-6676.pdf |
Description
| Title | Page 106 |
| Full text | 106 Figure 3.10: Trem2 and C1q deficiency independently affects Aβ proteostasis: Principal Component analysis was performed on the 7 Aβ ELISA measurements (Top). Clustering algorithms isolate Trem2 deficient animals apart from C1q deficient animals and are drawn on the graph. K-means clustering algorithms indicate the number of animals in in each cluster (Bottom). |
