Anomalous Amyloid-Beta Exposure And Bbb Insulin Resistance Induce Cerebrovascular Dysfunction In Alzheimer’S Disease
2024-04
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Anomalous Amyloid-Beta Exposure And Bbb Insulin Resistance Induce Cerebrovascular Dysfunction In Alzheimer’S Disease
Authors
Published Date
2024-04
Publisher
Type
Thesis or Dissertation
Abstract
Cerebrovascular dysfunction is increasingly recognized as an early event and a significant contributor to Alzheimer’s disease (AD). Mounting evidence has linked AD to type 2 diabetes mellitus (T2DM), both of which manifest insulin resistance in the blood-blood brain barrier (BBB) endothelium that lines the cerebrovascular lumen. While insulin signaling regulates amyloid-beta (Aβ) trafficking and accumulation at the BBB, enhanced accumulation of Aβ within the BBB endothelium may cause insulin resistance. However, the synergistic effect of Aβ exposure and disrupted insulin signaling on BBB dysfunctions during AD and T2DM remains unclear. This thesis aims to establish causal connections between insulin resistance, BBB dysfunction, and AD pathogenesis. A graphic abstract is provided in Figure 1.6. The first part of the thesis focuses on Aβ exposure at the BBB. We have employed dynamic SPECT/CT imaging and pharmacokinetic (PK) modeling to analyze trafficking of different Aβ isoforms. Our findings revealed that Aβ42 exhibited a greater propensity to accumulate in the BBB endothelium (Chapter 2). We further performed cellular uptake and molecular imaging studies to demonstrate that Aβ40 and Aβ42 employed distinct molecular pathways for cell entry and intracellular trafficking in the BBB endothelial cells (Chapter 3). The second part of the thesis characterizes the insulin signaling pathway at the BBB. We have mapped the dynamics of insulin-responsive pathways in BBB endothelial cells using time-series transcriptomic analysis. The results suggested that inflammation-related pathways are downregulated by insulin treatment (Chapter 4). Further, insulin was found to dose-dependently regulate the expression of vascular cell adhesion molecule 1 (VCAM1), which is an inflammatory marker. A systems biology model was established, and VCAM1 expression was quantitatively simulated under disease conditions by incorporating proteomics and transcriptomics data into the model (Chapter 5). The third part of the thesis explores the contributing role of other pathological conditions that manifest insulin resistance in causing BBB dysfunction. Our findings revealed that loss of endothelial-pericyte interaction was associated with disrupted insulin signaling in both cell types. Further, the balance between matrix metalloproteinases and their endogenous inhibitors was dysregulated to compromise BBB integrity (Chapter 6). To explore the role of dyslipidemia, we have evaluated the therapeutic benefits of APOA-I mimetic peptide 4F and found that 4F mitigated Aβ42 exposure at the BBB endothelium in AD mice, potentially via modulation of the endocytosis and exocytosis processes (Chapter 7). Taken together, these findings provide novel insights into how Aβ42 exposure and insulin resistance may synergistically contribute to BBB dysfunction and how other pathological conditions with insulin resistance exacerbate these processes. Such discoveries facilitate the understanding of cerebrovascular pathology in AD and the identification of novel therapeutic targets.
Keywords
Description
University of Minnesota Ph.D. dissertation. May 2024. Major: Pharmaceutics. Advisor: Karunya Kandimalla. 1 computer file (PDF); xx, 302 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Wang, Zengtao. (2024). Anomalous Amyloid-Beta Exposure And Bbb Insulin Resistance Induce Cerebrovascular Dysfunction In Alzheimer’S Disease. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/264372.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.