High-fat Diet-induced Diabetes Couples to Alzheimer’s Disease through Inflammation-activated C/EBPb/AEP Pathway Open Access

Abstract

Diabetes is a risk factor for Alzheimer's disease (AD), which is also known as type 3 diabetes and is characterized by insulin resistance and insulin signaling impairment in the brains of AD patients. However, the molecular mechanism coupling diabetes to AD is still unknown. In this dissertation study, I report that inflammation, which is linked to obesity and diabetes induced by high-fat diet (HFD), activates neuronal C/EBPb/AEP signaling that leads to AD pathologies and cognitive dysfunctions. In neuronal Thy1-C/EBPb transgenic (Tg) mice, HFD induces diabetes and insulin resistance, along with mouse Ab accumulation and hyperphosphorylated Tau aggregation in the brain, resulting in cognitive impairments. These effects are significantly diminished when AEP is deleted from C/EBPb Tg mice. Chronic treatment with inflammatory lipopolysaccharide (LPS) facilitates AD pathologies and cognitive disorders in C/EBPb Tg but not in wild-type mice, and these deleterious effects were substantially alleviated in C/EBPb Tg/AEP -/- mice. Remarkably, the anti-inflammatory drug aspirin strongly attenuates HFD- induced diabetes and AD pathologies in neuronal C/EBPb Tg mice. Therefore, the findings presented in this study demonstrate that inflammation-activated neuronal C/EBPb/AEP signaling couples diabetes to AD. 

Table of Contents

Table of Contents

CHAPTER 1: Background and Literature Review..................................................................................1

1.1 Abstract ................................................................................................................................. 2

1.2 Alzheimer’s disease............................................................................................................... 3

1.2.1 Global Impact and History of Alzheimer’s disease ....................................................... 3

1.2.2 Clinical Manifestation and Diagnosis of Alzheimer’s disease ...................................... 4

1.3 Alzheimer’s disease Pathology and Research ...................................................................... 7

1.3.1 Neuropathological Markers of Alzheimer’s disease...................................................... 7

1.3.2 Risk Factors of Alzheimer’s disease............................................................................ 11

1.3.3 Current treatments of Alzheimer’s disease .................................................................. 12

1.4 Alzheimer’s disease as Type 3 diabetes.............................................................................. 13

1.4.1 Type 2 diabetes (T2DM).............................................................................................. 13

1.4.2 Tissues implicated in diabetes ..................................................................................... 14

1.4.3 Insulin resistance.......................................................................................................... 16

1.4.4. Evidence of AD as Type 3 diabetes............................................................................ 18

1.4.5 The role of inflammation in diabetes, insulin resistance, and Alzheimer’s disease .... 21

1.5 The role of C/EBPb in Alzheimer’s disease and metabolic diseases.................................. 23

1.5.1 C/EBPb: General Introduction..................................................................................... 23

1.5.2 The role of C/EBPb in Alzheimer’s disease ................................................................ 24

1.5.3 The role of C/EBPb in inflammation and metabolism ................................................ 25

1.5.4 C/EBPb regulates AEP expression .............................................................................. 26

1.6 The role of Asparagine endopeptidase (AEP) in Alzheimer’s disease ............................... 27

1.6.1 AEP: General Introduction .......................................................................................... 27

1.6.2 AEP-cut APP and tau promote Alzheimer’s disease pathogenesis ............................. 28

1.6.3 The Role of AEP in Metabolic Diseases...................................................................... 29

1.7 Dissertation Overview .................................................................................................... 30

CHAPTER 2: Materials and Method...........................................................................................................31

2.1 Animals ............................................................................................................................... 32

2.2 LPS treatment...................................................................................................................... 33

2.3 HFD treatment .................................................................................................................... 33

2.4 AEP activity assay............................................................................................................... 35

2.5 Immunoblotting analysis..................................................................................................... 35

2.6 Metabolic Measurements .................................................................................................... 36

2.7 Glucose and insulin tolerance tests .................................................................................... 36

2.8 Immunostaining and Thioflavin S staining ......................................................................... 36

2.9 Oil red O staining ............................................................................................................... 37

2.10 H&E staining .................................................................................................................... 37

2.11 Golgi staining ................................................................................................................... 38

2.12 Morris Water Maze ........................................................................................................... 38

2.13 Fear conditioning tests ..................................................................................................... 39

2.14 High-performance lipid chromatography (HPLC) analysis............................................. 40

2.15 Quantification and Statistical Analysis............................................................................. 41

2.16 Key Reagent and Resource ............................................................................................... 41

CHAPTER 3: The role of C/EBPb/delta-secretase signaling in HFD-induced diabetes and insulin resistance ...................................................................................................................................................45

3.1 Introduction......................................................................................................................... 46

3.2 Results ................................................................................................................................. 47

3.2.1 High-Fat Diet (HFD) induces diabetes in Thy1-C/EBPb transgenic mice .................... 47

3.2.2 High-Fat Diet (HFD) diminishes AMPK/ACC pathway and impairs insulin signaling in Thy1-C/EBPb transgenic mice ......................................................................................... 60 3.2.3 Knockout of AEP in Thy1-C/EBPb transgenic mice alleviates HFD-induced neuro- inflammation and AD pathologies ........................................................................................ 68

CHAPTER 4: HFD-induced diabetes triggers AD pathology through inflammation- activated C/EBPb/delta-secretase pathway................................................................................................78

4.1 Introduction......................................................................................................................... 79

4.2 Results ................................................................................................................................. 80

4.2.1 Deletion of AEP from Thy1-C/EBPb transgenic mice ameliorates HFD-triggered synaptic degeneration and cognitive dysfunctions ............................................................... 80 4.2.2 LPS triggers APP and Tau cleavage and neuro-inflammation in Thy1-C/EBPb transgenic mice via activation of C/EBPb/AEP signaling.................................................... 86

4.2.3 LPS induces AD pathologies and cognitive deficits in Thy1-C/EBPb transgenic mice ............................................................................................................................................... 92

4.2.4 NSAID aspirin abrogates HFD-induced inflammation, diabetes, and AD pathologies in Thy1-C/EBPb transgenic mice ....................................................................................... 100

CHAPTER 5: Conclusion and Discussion................................................................................................110

5.1 Conclusion and discussion of the dissertation study ........................................................ 111

5.2 AEP’s role in provoking pathogenesis in Alzheimer’s disease......................................... 122

5.2.1 AEP phosphorylation by SRPK2 enhances its enzymatic activity, provoking pathogenesis in Alzheimer’s disease .................................................................................. 122

5.2.2 AEP cleavage of TrkB receptor abolishes its phosphorylation of APP, aggravating Alzheimer’s disease pathologies......................................................................................... 137

5.3 Limitations and Future Directions.................................................................................... 146

REFERENCES ....................................................................................................................................................148 

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Keyword	Alzheimer's disease
Committee Chair / Thesis Advisor	English, Art, Emory University Ye, Keqiang, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Committee Members	Chin, Lih-Shen, Emory University Benian, Guy, Emory University Hall, Randy, Emory University

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	High-fat Diet-induced Diabetes Couples to Alzheimer’s Disease through Inflammation-activated C/EBPb/AEP Pathway ()	2022-05-17 15:34:45 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions